At least partially resorbable reticulated elastomeric matrix elements and methods of making same

ABSTRACT

The present disclosure relates to reticulated elastomeric matrices, and more particularly to at least partially degradable elastomeric elements that are compressible and exhibit resilience in their recovery and that can be employed in diverse applications including, without limitation, biological implantation, especially in humans.

FIELD OF THE INVENTION

The present disclosure relates to reticulated elastomeric matrices, andmore particularly to at least partially degradable elastomeric elementsthat are compressible and exhibit resilience in their recovery and thatcan be employed in diverse applications including, without limitation,biological implantation, especially in humans.

BACKGROUND OF THE INVENTION

There is a current need in medicine for innocuous implantable devicesthat can be delivered to an in vivo patient site, for example, a site ina human patient, that can occupy that site for extended periods of timewithout being harmful to the host. There is currently a further need forsuch innocuous implantable devices that can eventually becomeintegrated, such as biointegrated, e.g., ingrown with tissue orbio-integration but which is also at least partially degradable orbioabsorbable to allow for further tissue ingrowth, as well as a currentneed for biodegradable or absorbable porous polymeric materials fortissue augmentation and repair.

Various tissue engineering (TE) approaches are reviewed in co-pendingU.S. Patent Application Publications US 2005/0043816 and US2007/0190108and PCT application filed Feb. 10, 2010 under Attorney Docket Number14596-105013. Tissue engineering generally includes the delivery of abiocompatible tissue substrate that serves as a scaffold or support ontowhich cells may attach, grow and/or proliferate, thereby synthesizingnew tissue by regeneration or new tissue growth to repair a wound ordefect. Open cell biocompatible foams have been recognized to havesignificant potential for use in the repair and regeneration of tissue.Tissue engineering has tended to focus on synthetic bioabsorbablematerials because they tend to be absorbed and metabolized by the bodywithout causing significant adverse tissue responses.

Bioabsorbable TE scaffolds have been made using various processingmethods and materials such as those described in U.S. Pat. No. 5,522,895(Mikos), U.S. Pat. No. 5,514,378 (Mikos et al.), U.S. Pat. No. 5,133,755(Brekke), U.S. Pat. No. 5,716,413 (Walter et al.), U.S. Pat. No.5,607,474 (Athanasiou et al.), U.S. Pat. No. 6,306,424 (Vyakarnam et.al), U.S. Pat. No. 6,355,699 (Vyakarnam et. al), U.S. Pat. No. 5,677,355(Shalaby et al.), U.S. Pat. No. 5,770,193 (Vacanti et al.), and U.S.Pat. No. 5,769,899 (Schwartz et al.). Synthetic bioabsorbablebiocompatible polymers used in the above-mentioned references are wellknown in the art and, in most cases, include aliphatic polyesters,homopolymers and copolymers (random, block, segmented and graft) ofmonomers such as glycolic acid, glycolide, lactic acid, lactide (d-, l-,meso-, or a mixture thereof), ε-caprolactone, trimethylene carbonate,and p-dioxanone.

Bioabsorbable polyurethane have been made using various processingmethods and materials such as those described in U.S. Pat. No. 7,425,288(Flodin et al.) and U.S. Pat. No. 6,210,441 (Flodin), U.S. Pat. No.6,221,997 (Woodhouse, et al), US 2007/0299151 (Guelcher, et al), US2010/0068171 (Guelcher, et al), U.S. Pat. No. 7,264,823 (Beckman et al),US 2005/0013793 (Beckman et al), WO 2009/141732 (Van Beijma), WO2004/074342 (Heijkants, et. al.), US 2010/0068171 (Guelcher, et al), US2006/0188547 (Bezwada), and US 2009/0292029 (Bezwada).

Various polymers having varying degrees of biodurability are known.However, some materials are undesirable in view of adverse tissueresponse during the product's life cycle as the polymers biodegrade. Thedegradation characteristics of certain materials resist engineering,thus severely limiting their ability to serve as effective scaffolds.Also, there remains a need for an implant that withstands compression ina delivery-device during delivery to a biological site, e.g., by acatheter, endoscope, arthoscope, or syringe, but is capable of expansionby resiliently recovery to occupy and remain in the biological site.Moreover, it has been difficult to engineer controlled pore sizes suchthat the implant becomes ingrown with tissue, in situ. Furthermore, manymaterials produced from polyurethane foams formed by blowing during thepolymerization process are unattractive from the point of view ofbiodurability because undesirable materials that can produce adversebiological reactions are generated during polymerization, for example,carcinogens, cytotoxins and the like.

SUMMARY OF THE INVENTION

The present disclosure addressed many of the limitations of the priorart.

According to an aspect, the disclosure provides a matrix comprising abiocompatible, cross-linked, biodegradable polyurethane, the matrixhaving a continuous-interconnected void phase, wherein the matrix isconfigured to be in-grown by a biological tissue. According to anaspect, the polyurethane degrades in a body of an animal to cause a lossof weight of the matrix and the resultant void phase is further ingrownand proliferated by tissues or biological tissue and in one embodiment,further ingrown and proliferated tissues can re-model to becomesubstantially similar to the surrounding tissue in the body of an animalwhere it was placed. According to an aspect, the polyurethane matrix isreticulated to a Darcy permeability of at least 100 or in oneembodiment, at least 150 or in another embodiment, at least 200.

According to an aspect, the polyurethane matrix comprises biodegradable,polyol-derived soft segments and an isocyanate-derived hard segments.According to an aspect, the matrix has substantially non-crystallineisocyanate-derived hard segments. According to an aspect, thepolyurethane matrix is derived from an amount of glycerol sufficient toat least partially cross-link the isocyanate-derived hard segments.According to an aspect, the isocyanate-derived hard segments aresubstantially free from biuret and/or allophanate and/or isocyanurategroups.

According to an aspect of the disclosure, the isocyanate hard segment isat least partially non-crystalline. According to an aspect of thedisclosure, the isocyanate hard segment is at least partially composedof 4,4-MDI and 2,4-MDI. According to an aspect of the disclosure, the2,4-MDI is included in an amount sufficient to render the hard segmentsubstantially non-crystalline. According to an aspect of the disclosure,the 2,4-MDI is present at from about 5% to about 50% relative to theamount of 4,4-MDI. According to an aspect of the disclosure, MDI-derivedhard segment are biostable.

According to an aspect of the disclosure, the isocyanate hard segment isat least partially biodegradable. According to an aspect of thedisclosure, the isocyanate hard segment is composed of monomerscontaining at least one hydrolysable bond. According to an aspect,biodegradable hard segments may be formed from an aliphatic diisocyanateis selected from the group consisting of lysine methyl esterdiisocyanate, lysine triisocyanate, 1,4-diisocyanatobutane, and mixturesthereof. According to an aspect, biodegradable hard segments may beformed from an aromatic diisocyanate is a hydrolytically-cleavable,bridged diphenyl diisocyanate. According to an aspect, the aromaticdiisocyanate may be a hydrolytically-cleavable, bridged diphenyldiisocyanate.

According to an aspect of the disclosure, the at least partiallybiodegradable, reticulated, elastomeric, polyurethane matrix containssoft segments derived from hydrolyzable polyols. According to an aspectof the disclosure, the polyols contain one or more tertiary carbonlinkages. According to an aspect of the disclosure, the polyol softsegments will at least partially degrade. According to an aspect of thedisclosure, the polyol soft segments may be derived from at least onemoiety derived from the group consisting of a a polyester polyol,polycaprolactone polyol, a poly(caprolactone-co-glycolide)polyol, apoly(caprolactone-co-l-lactide)polyol, apoly(caprolactone-co-d-l-lactide)polyol,poly(caprolactone-co-paradioxanone polyol and copolymers and mixturesthereof.

According to an aspect of the disclosure, the polyol soft segments maycontain one or more tertiary carbon linkages.

According to an aspect of the disclosure, the at least partiallybiodegradable, reticulated, elastomeric, polyurethane matrix has anisocyanate index less than or equal to 1.05 or in another embodimentless than 1.02.

According to an aspect of the disclosure, the at least partiallybiodegradable, reticulated, elastomeric, polyurethane matrix may furthercontain a chain extender. According to an aspect of the disclosure, theat least partially biodegradable, reticulated, elastomeric, polyurethanematrix may further comprise a cross-linker in addition to glycerol.

According to an aspect of the disclosure, the at least partiallybiodegradable, reticulated, elastomeric, polyurethane matrix furthercomprising a blowing agent. The blowing agent may be water.

According to an aspect of the disclosure, the at least partiallybiodegradable, reticulated, elastomeric, polyurethane matrix may furthercomprise at least one at least one auxiliary agent which may includesurfactants, cell-openers, viscosity modifiers, blowing catalysts, andgelling catalysts.

According to an aspect, the disclosure provides methods of making thepartially biodegradable, reticulated, elastomeric, polyurethane matrix.According to an aspect, there is provided a mixture of diisocyanatesthat polymerize to yield non-crystalline hard segments. According to anaspect, there is provided a mixture of hydrolyzable polyols. Thedisclosure provides for reacting the isocyanates and polyols to form anat least partially biodegradable polyurethane foam. Moreover, thereaction proceeds so that the resultant foam is substantially free ofun-reacted isocyanate groups, biuret groups, allophanate groups, and/orisocyanurate group. According to an aspect, the methods further providefor reticulating the foam to a Darcy permeability of at least 100.

According to an aspect, the disclosure provides devices made from thedisclosed a partially biodegradable, reticulated, elastomeric,polyurethane matrix. According to an aspect, the devices includeartificial tissues.

According to an aspect, the disclosure provides a process for preparinga biocompatible, cross-linked, biodegradable polyurethane, the matrixhaving a continuous-interconnected void phase, wherein said matrix isconfigured to be in-grown by a biological tissue the process comprisingproviding a biodegradable polyol having a molecular weight of at least750, admixing an isocyanate component, wherein said isocyanate reacts toform substantially non-crystalline hard segments, admixing a glycerolcross-linker, admixing a blowing agent, and reacting said admixture toform a biocompatible, cross-linked, biodegradable polyurethane foam.

According to an aspect of the method, the foam is reticulated. Accordingto an aspect of the method, the foam is reticulated to a Darcy value ofat least 100. According to an aspect of the method, the foam isreticulated by contact with a mixture of explosive gases containinghydrogen and oxygen. According to an aspect of the method, the foam isreticulated by detonation of the explosive gas mixture.

According to an aspect, a medical device is provided. According to anaspect, the medical device has a matrix comprising a biocompatible,cross-linked, biodegradable polyurethane, the matrix having acontinuous-interconnected void phase, wherein said matrix is configuredto be in-grown by a biological tissue. The continuous-interconnectedvoid phase is termed as reticulated matrix and is interconnected andintercommunicating networks of cells, pores, and voids to permitingrowth and proliferation of tissue into the matrix interiors or in oneembodiment into the device interiors.

According to an aspect, a method of treating a tissue defect isprovided. According to an aspect, the method comprises providing amedical device to an in vivo site of a tissue defect, said medicaldevice having a matrix comprising a biocompatible, cross-linked,biodegradable polyurethane, the matrix having acontinuous-interconnected void phase, wherein said matrix is configuredto be in-grown by a biological tissue.

Still other aspects and advantages of the present invention will becomereadily apparent by those skilled in the art from the following detaileddescription, wherein it is shown and described preferred embodiments ofthe invention, simply by way of illustration of the best modecontemplated of carrying out the invention. As will be realized theinvention is capable of other and different embodiments, and its severaldetails are capable of modifications in various obvious respects,without departing from the invention. Accordingly, the description is tobe regarded as illustrative in nature and not as restrictive.

BRIEF DESCRIPTION OF THE DRAWINGS

Some embodiments of the invention, and of making and using theinvention, are described in detail below, which description is to beread with and in the light of the foregoing description, by way ofexample, with reference to the accompanying drawings in which:

FIG. 1 is a schematic depiction of an example of a particular morphologyof a reticulated matrix which illustrates some of the features andprinciples of the microstructure of embodiments of the invention.

FIG. 3 presents electron micrographs of an unreticulated matrix

FIG. 2 presents electron micrographs of exemplary reticulated matrix ofthe invention.

It is to be noted, however, that the appended drawings illustrate onlytypical embodiments of this invention and are therefore not to beconsidered limiting of its scope, for the invention may admit to otherequally effective embodiments.

DETAILED DESCRIPTION OF THE INVENTION

The present disclosure relates to a cross-linked polyurethane foam. Thepresent disclosure thus differs from e.g., Flodin, U.S. Pat. No.7,425,288, and Chun, U.S. 2004/0175408 who disclose solvent-solublepolyurethanes and from e.g., Woodhouse, U.S. Pat. No. 6,221,997, whodiscloses melt-processable and solution-castable polyurethane polymers.

The present disclosure relates to polyurethanes synthesized fromhigh-molecular weigh polyols, e.g., polyoly having a molecularweight >300. The present disclosure differ from polyurethanessynthesized from low-molecular weight polyols. i.e., those such asdisclosed by Guelcher, U.S. 2009/0221784.

The present disclosure relates to polyurethanes synthesized at lowisocayanate ratios, e.g., 1.05 or less, thereby substantially orcompletely preventing the formation of allophanate, and/or biuret,and/or isocyanurate linkages. Therefore, the polyurethanes of thepresent disclosure differ from those such as disclosed by Brady, U.S.Pat. No. 6,177,522.

The present disclosure relates to bioabsorbable polyurethanes and thusdiffer from the biostable polyurethanes such as disclosed by Bowman,U.S. Pat. No. 6,852,330 and Pinchuk, U.S. Pat. No. 6,545,097.

The present disclosure relates to reticulated polyurethane foams havinga continuous void phase comprising at least 75% of the total volume. Thefoams of the present disclosure are characterized by a Darcypermeability of at least 200. Brady, U.S. 2005/0072550 discloses a foamreticulated by crushing. Brady does not disclose a Darcy value for hisfoam. However, crushing generally achieves low Darcy valuesapproximately 10-15.

The present disclosure relates to a resilient, elastomeric foam that issynthesized in the presence of a blowing agent to form a foam. In asubsequent process step. The foam is infused with an explosive mixture,e.g., H₂ and O₂ which is ignited to reticulate the foam. Thepost-processing steps provide a foam that may be implanted into a body,such as a human body. However, the foam differs from prior art foamsthat may be injected into the body. The requirement for explosivereticulation means that the foam cannot be formed in situ, in an animalbody.

Certain embodiments of the invention comprise at least partiallydegradable reticulated elastomer products, which are also compressibleand exhibit resilience in their recovery, that have a diversity ofapplications and can be employed, by way of example, in biologicalimplantation, especially into humans, for long-term tissue engineering(TE) implants, especially where dynamic loadings and/or extensions areexperienced, such as in soft tissue related applications; repair of softtissue defects, specifically inguinal, femoral, ventral, incisional,umbilical, and epigastric hernias; surgical meshes for tissueaugmentation, support and repair; wound healing and defect filling, fortherapeutic purposes; for cosmetic, reconstructive, urologic orgastroesophageal purposes; or as substrates for pharmaceutically-activeagents, e.g., drug, delivery. The resilience of the at least partiallydegradable reticulated elastomeric matrix also allows recovery if it iscompressed during delivery and once it is placed in the human or animalbody.

In another embodiment, least partially degradable reticulated elastomerproducts such as a dressing-scaffold can be uses as an implantabledressing in Negative Pressure Wound Therapy (NPWT) for the treatment ofadvanced wounds such as diabetic ulcers, decubitus ulcers (pressuresores), and venous & arterial ulcers. Other embodiments involvereticulated, at least partially degradable elastomer products for invivo delivery via catheter, endoscope, arthoscope, laproscope,cystoscope, syringe or other suitable delivery-device and can besatisfactorily implanted or otherwise exposed to living tissue andfluids for extended periods of time.

There is a need in medicine, as recognized by the present invention, forinnocuous implantable devices that can be delivered to an in vivopatient site, for example a site in a human patient, that can occupythat site for extended periods of time without being harmful to thehost. In one embodiment, such implantable devices are allowed toeventually become integrated, such as biointegrated, e.g., ingrown withtissue or bio-integration. In one embodiment, such implantable devicescan at least partially degrade or bioabsorb to allow for further tissueingrowth and in yet another embodiment, such implantable devices canfully degrade or bioabsorb to allow for even further tissue ingrowth.Various biodegradable or absorbable porous polymeric materials areproposed for tissue augmentation and repair.

In one embodiment of the invention the at least partially degradable orfully resorbable matrix can be employed as a hybrid dressing scaffoldmaterial for the treatment of chronic ulcers that form in patients dueto impaired peripheral vascular perfusion. These ulcers can be diabeticulcers, decubitus ulcers, or arterial/venous insufficiency ulcers.Current treatments of these very difficult to heal wounds involves theapplication of vacuum (negative pressure wound therapy—NPWT) to thewound bed through a non-resorbable foam or gauze dressing. This methodtreatment presents two complications, ie., significant pain duringdressing changes since tissue grows into the pores/interstices of thecurrently used dressings in NPWT, and prolonged inflammation of the siteas a result of the inadvertent damage during dressing change. Aresorbable elastomeric matrix as proposed in the current inventionaddress both these important clinical unmet needs by service as a“stay-in-place” dressing-scaffold that enables delivery of NPWT to thewound bed and at the same time serving as a scaffold to promote tissueingrowth that is eventually resorbed at a controlled degradation rate.

In another embodiment of the invention, the at least partiallydegradable or fully resorbable elastomeric matrix can be used forapplications as a three dimensional tissue filler to support tissueingrowth at sites of excisional biopsies done for cancer diagnosis andtherapy. This includes applications in breast cancer therapy such aslumpectomies and other procedures that involve removal of significantamounts of connective tissue. Other similar applications are in thefield of plastic surgery wherein the elastomeric matrix can be used tofill tissue defects created at the donor site in tram flap procedures

In another embodiment of the invention, the at least partiallydegradable or fully resorbable elastomeric matrix can be used forapplications in general surgery involving the repair and reinforcementof soft tissue defects at sites that are highly prone to infection.These include repair of complex incisional hernias, gastrointestinalfistulas, anal fistulas and enterocutaneuous fistulas. All theseapplications require a resorbable elastomeric matrix material that fillsthe 3-dimensional defect site, engenders tissue ingrowth, and degradesat a predetermined rate to allow the remodeling of the extracellularmatrix that is laid down during the early phases of wound healing

In another embodiment of the invention, the at least partiallydegradable or fully resorbable elastomeric matrix can be used forapplications in repair of orthopedic soft tissues such as tendons,ligaments, meniscus, intervertebral disk, and articular cartilage. Ineach of these applications, the elastomeric matrix can also be implantedand deliver various bioactive and cellular components such as plateletrich plasma, platelet rich fibrin matrix, growth factors (PDGF, FGF) toimprove the regeneration of tissue in avascular zones.

In another embodiment of the invention, the at least partiallydegradable or fully resorbable elastomeric matrix can be used forendovascular and cardiovascular/neurovascular applications such asaneurysm occlusion, closure of atrial and ventricular septal defects,closure of arteriotomy sites, vascular occlusion, etc.

In another embodiment of the invention, the at least partiallydegradable or fully resorbable elastomeric matrix can be used fordelivery of adult cells, adult mesenchymal and hematopoetic stem cells,differentiated cells derived from induced Pluripotent Stem (iPS) cellsas well as those derived from human embryonic stem cells (hESC) totarget sites for therapeutic purposes. Applications include (but are notlimited to) delivery of iPS derived pancreatic islet cells into liverparenchyma for curing Type 1 and Type 2 diabetes, delivery of cardiacmyocytes into regions of cardiac muscle that have ischemic damageresulting from infarcts, delivery of stem cells for guided nervegeneration in the peripheral nervous system, and spinal cordregeneration applications.

In another embodiment of the invention, the at least partiallydegradable or fully resorbable elastomeric matrix can be used as acarrier for various various bioactive agents and proteins/peptidesapplied as coatings to the elastomeric matrix substrate or viaimmobilization/attachment of functionalized end groups. Applicationsenvisioned include promotion of selective cellular membrane integrinreceptor adhesion, improved biocompatibility for blood contactingapplications, enhanced cellular activity and synthesis of extracellularmatrix proteins, and leveraging these benefits to accelerate the repairprocess in tissues.

It would be desirable to form implantable devices suitable for use astissue engineering scaffolds, or other comparable substrates, to supportin vivo cell propagation applications, for example, in a large number oforthopedic applications especially in soft tissue attachment,regeneration, augmentation, support and ingrowth of a prosthetic organ.In another embodiment, it would also be desirable to form implantabledevices suitable for use as tissue engineering to support in vivo cellor tissue propagation applications, for example in a large number ofsurgical or wound healing applications, such as healing of tissue whereweakness exists in the cases of repair of soft tissue defects such asnumber of hernia applications, surgical meshes for augmentation Withoutbeing bound by any particular theory, having a high void content and ahigh degree of reticulation allowing unfettered access to theinter-connected and inter-communicating high void content is thought toallow the implantable device to become at least partially ingrown and/orproliferated, in some cases substantially ingrown and proliferated.Without being bound by any particular theory, the reticulatedimplantable devices having a high void content and a high degree ofreticulation or inter-connectivity and inter-communication between thesevoids that can be accessed by the in vivo cell or tissue propagation isthought to allow the implantable device to become at least partiallyingrown and/or proliferated, in some cases substantially ingrown andproliferated, in other cases completely ingrown and proliferated, withcells including tissues such as fibroblasts, fibrous tissues, synovialcells, bone marrow stromal cells, stem cells and/or fibrocartilagecells. The ingrown and/or proliferated tissues thereby providefunctionality, such as load bearing capability, for defect repair of theoriginal tissue that is being repaired or replaced. Owing to thebiointegrative three dimensional inter-connected and inter-communicatingstructure characteristics of the base reticulated implantable devices,embodiments of the invention have the advantage of potentially betterand faster tissue in-growth, healing, and remodeling. The high degree ofinitial inter-connected and inter-communicated accessible void contentcan be enhanced by further at least partial degradation, at leastpartial absorption or complete degradation and absorption of theimplantable device. This at least partial degradation or absorptionultimately leads to further enhancement of the already high void contentof the reticulated matrix with its high degree of inter-connectivityleading to higher volume of tissue incorporation and less-hinderedbio-integration. The tissue incorporation and less-hinderedbio-integration is even further enhanced by progressive degradation andabsorption that occurs in case of both partial or complete degradationand absorption.

In one aspect of this invention, the at least partially degradablereticulated elastomeric matrix which is designed to support tissueingrowth may contain at least one functional element that is useful ornecessary for the intended for repair of the targeted tissue defects. Inone embodiment, the functional element is a reinforcing element that canbe fiber or a mesh designed to enhance the mechanical load bearingfunctions such as strength, stiffness, tear resistance, burst strength,suture pull out strength, etc. Such reinforcements may made from eitherbe permanent or resorbable copolymers and homopolymers. In otherembodiments, the functional element is a thin layer, coating or film ofeither a permanent polymer or biodegradable polymer or a bioactivepolymer or a biopolymer or biologically derived collagen used to reducethe potential for adhesions, reduce the potential for biologicaladhesions and enhance tissue response. In yet another embodiment, thefunctional element is a polymeric and/or metallic structures used toimpart shape memory or structural support during delivery or placementof the device; and markers including dyes used to differentiate betweentwo sides of a mesh which may have differing characteristics. In oneembodiment, one or all or at least a selected number of the functionalelements can be incorporated into the least partially degradablereticulated elastomeric matrix. Any of these preferred functionalelements may be incorporated with the least partially degradablereticulated elastomeric matrix using various processing techniques knownin the art including adhesive bonding, melt processing, compressionmolding, solution casting, thermal bonding, suturing, and othertechniques.

In one embodiment, in some orthopedic applications such as rotator cuffrepair or repair of soft tissue defects such as number of herniaapplications where the implantable device serves in an augmentary role,precise fitting may not be required to match or fit the tissue that isbeing repaired or regenerated. The resilient nature of the matrix allowsfor the device or the material to follow the contour of the target sitein the body and one embodiment, fills the target space at it can providea fit and in another embodiment, the resilient nature of the matrixallows for recover from the first shape to the second shape. In anotherembodiment, an implantable device containing a reinforced reticulatedelastomeric matrix is shaped prior to its use, such as in surgicalrepair of tendons and ligaments or in repair of soft tissue defects,specifically inguinal, femoral, ventral, incisional, umbilical, andepigastric hernias; meshes for tissue augmentation, support and repair.One exemplary method of shaping is trimming. When shaping is desired,the reinforced reticulated elastomeric matrix can be trimmed in itslength and/or width direction along the lines or reinforcing fibers. Inone embodiment, this trimming is accomplished so as to leave about 2 mmoutside the reinforcement border, e.g., to facilitate suture attachmentduring surgery. In another embodiment, when shaping is desired, thereinforced reticulated elastomeric matrix can be trimmed along itslength and/or width direction, along any other regular curved dimensionssuch as circle or ellipse or along any irregular shape.

Broadly stated, certain embodiments of the reticulated, at leastpartially degradable elastomeric products of the invention comprise orare largely if not entirely, constituted by a highly permeable,reticulated matrix formed of an at least partially degradable polymericelastomer that is resiliently-compressible so as to regain its shapeafter delivery to a biological site. In one embodiment, the elastomericmatrix has good fatigue resistance associated with dynamic loading. Inanother embodiment, the elastomeric matrix is chemicallywell-characterized. In another embodiment, the elastomeric matrix isphysically well-characterized. In another embodiment, the elastomericmatrix is chemically and physically well-characterized.

Certain embodiments of the invention can be used to support cell growthand permit cellular ingrowth and proliferation in vivo and can be usefulas in vivo biological implantable devices, for example, for tissueengineering scaffolds that may be used in vitro or in vivo to provide asubstrate for cellular propagation.

The implantable devices of the invention can be useful for manyapplications as long-term tissue engineering implants, especially wheredynamic loadings and/or extensions are experienced, such as in softtissue related orthopedic applications for repair and regeneration. Insome embodiments, the reticulated elastomeric matrices of the presentinvention are as described in U.S. patent application Ser. No.10/848,624, filed May 17, 2004 (published as U.S. Patent ApplicationPublication No. U.S. 2005-0043816-A1 on Feb. 24, 2005), and U.S. PatentApplication Publication No. 2007/0190108 filed on Jan. 7, 2007, thedisclosures of each of which are hereby incorporated herein by thisreference in their entireties for all purposes.

In one embodiment, the at least partially degradable reticulatedelastomeric matrix of the invention can be used to facilitate tissueingrowth by providing a surface for cellular attachment, migration,proliferation and/or coating (e.g., collagen) deposition. In anotherembodiment, any type of tissue is allowed to grow into an implantabledevice comprising an at least partially degradable reticulatedelastomeric matrix of the invention, including, by way of example,epithelial tissue (which includes, e.g., squamous, cuboidal and columnarepithelial tissue), connective tissue (which includes, e.g., areolartissue, dense regular and irregular tissue, reticular tissue, adiposetissue, cartilage and bone), and muscle tissue (which includes, e.g.,skeletal, smooth and cardiac muscle), or any combination thereof, e.g.,fibrovascular tissue. In another embodiment of the invention, animplantable device comprising an at least partially degradablereticulated elastomeric matrix of the invention can be used to havetissue ingrowth substantially throughout the volume of itsinterconnected pores.

In one embodiment, the invention comprises an implantable device havingsufficient resilient compressibility to be delivered by a“delivery-device”, i.e., a device with a chamber for containing anelastomeric implantable device while it is delivered to the desired sitethen released at the site, e.g., using a catheter, endoscope,arthoscope, laproscope, cystoscope or syringe. In another embodiment,the thus-delivered elastomeric implantable device substantially regainsits shape after delivery to a biological site and has adequatebiodurability and biocompatibility characteristics to be suitable forlong-term implantation.

In another embodiment, the thus-delivered elastomeric implantable devicesubstantially regains its shape after delivery to a biological site andhas adequate biocompatibility as it degrades or absorbs over time. Inanother embodiment, the thus-delivered elastomeric implantable devicecan span defects and serve to bridge a gap or a defect in the nativetissue.

The structure, morphology and properties of the elastomeric matrices ofthis invention can be engineered or tailored over a wide range ofperformance by varying the starting materials and/or the processingconditions for different functional or therapeutic uses. The wide rangeof performance can include but not limited to loading, delivery andplacement of the device as well as the biocompatible in vivofunctionality ranging from cellular attachment, tissue ingrowth andproliferation to degree and time of degradation and absorption.

Without being bound by any particular theory, it is believed that an aimof the invention, i.e., to provide a light-weight structure, parts ofwhich are durable and parts of which are partially or fully degradableover time and that can be used to fill a biological volume or cavity ordefects and containing sufficient porosity distributed throughout thevolume, can be fulfilled by permitting one or more of: occlusion,embolization, cellular ingrowth, cellular proliferation, tissueregeneration, cellular attachment, drug delivery, enzymatic action byimmobilized enzymes, and other useful processes as described hereinincluding, in particular, the applications to which priority is claimed.The available space for this light-weight structure for cellularingrowth, cellular proliferation, tissue regeneration and cellularattachment increases over time progressively encompassing the biologicalvolume or cavity or defects.

In one embodiment, elastomeric matrices of the invention have sufficientresilience to allow substantial recovery, e.g., to at least about 50% ofthe size of the relaxed configuration in at least one dimension, afterbeing compressed for implantation in the human body, for example, a lowcompression set, e.g., at 25° C. or 37° C., and sufficient strength andflow-through for the matrix to be used for controlled release ofpharmaceutically-active agents, such as a drug, and for other medicalapplications. In another embodiment, elastomeric matrices of theinvention have sufficient resilience to allow recovery to at least about60% of the size of the relaxed configuration in at least one dimensionafter being compressed for implantation in the human body. In anotherembodiment, elastomeric matrices of the invention have sufficientresilience to allow recovery to at least about 90% of the size of therelaxed configuration in at least one dimension after being compressedfor implantation in the human body. In yet another embodiment,elastomeric matrices of the invention have sufficient resilience toallow recovery to at least about 95% of the size of the relaxedconfiguration in at least one dimension after being compressed forimplantation in the human body.

In the present application, the elastomers and other products areinitially stable for extended periods of time in a biologicalenvironment but eventually will show partial degradation or completedegradation. Such products should not exhibit significant symptoms ofbreakdown or degradation, erosion or significant deterioration ofmechanical properties relevant to their employment when exposed tobiological environments for periods of time that may be weeks or monthsor even a few years. As the device or the product partially degrades orabsorbs commensurate with the use of the implantable device, thenon-degradable part or the remaining part of the device or products arestable and biocompatible for extended periods of time in a biologicalenvironment and do not exhibit significant symptoms of breakdown ordegradation or erosion when exposed to biological environments forperiods of time commensurate with the use of the implantable device. Thedegradable part of the device or the product absorbs in a biocompatiblefashion over a period of time and in one embodiment over a long periodof time exceeding at least one or at least two or at least three years.The period of implantation may be weeks or months or a few years; thelifetime of a host product in which the elastomeric products of theinvention are incorporated, such as a graft or prosthetic; or thelifetime of a patient host to the elastomeric product. In oneembodiment, the desired period of exposure is to be understood to be atleast partially about 29 days. In another embodiment, the desired periodof exposure is to be understood to be at least partially 29 days. In oneembodiment, the implantable device is biodurable at least partially forat least 2 months. In another embodiment, the implantable device isbiodurable at least partially for at least 6 months. In anotherembodiment, the implantable device is biodurable at least partially forat least 12 months. In another embodiment, the implantable device isbiodurable at least partially for longer than 12 months. In anotherembodiment, the implantable device is biodurable for at least at leastpartially 24 months. In another embodiment, the parts of the implantabledevice are biodurable at least partially for at least 5 years. Inanother embodiment, the parts of the implantable device are biodurableat least partially for longer than 5 years. In another embodiment, theentire implantable device degrades or bioabsorbs completely over time ina biocompatible fashion.

In one embodiment, the products of the invention are also biocompatible.In the present application, the term “biocompatible” means that theproduct induces few, if any, adverse biological reactions when implantedin a host patient. Employment of an implant that can support invasion offibroblasts and other cells enables the implant to eventually become abiointegrated part of the healed aneurysm. The implant can bebiocompatible and elicit no adverse biological response on delivery orafter occlusion and the healing of the aneurysm.

In one embodiment, biodurable part of the partially degradablereticulated elastomeric matrix of this invention is also biocompatible.In another embodiment, the non-degradable or the no-resorbable or thebiostable part of the partially degradable reticulated elastomericmatrix of this invention is also biocompatible. In the presentapplication, the term “biocompatible” means that the product inducesfew, if any, adverse biological reactions when implanted in a hostpatient. Similar considerations applicable to “biodurable” also apply tothe property of “biocompatibility”. The non-degradable or theno-resorbable or the biostable part comprises the hard segment of thepartially degradable reticulated elastomeric matrix. The hard segmentcomprises non-degradable isocyanate-derived hard segment.

The biodegradable components of the at least partially degradableelastomeric matrix can degrade by hydrolysis or by enzymatic activity.In one embodiment, the biodegradable components of the at leastpartially degradable elastomeric matrix can bio-degrade or may be brokendown into innocuous, nontoxic or biocompatible products. The degradationproduct is not allowed to evoke unusual inflammatory response/toxicresponse and is metabolized by the body in a biocompatible fashion andis characterized by the absence of or extremely low: cytotoxicity,hemotoxicity, carcinogenicity, mutagenicity, or teratogenicity.

An intended biological environment can be understood to be in vivo,e.g., that of a patient host into which the product is implanted or towhich the product is topically applied, for example, a mammalian hostsuch as a human being or other primate, a pet or sports animal, alivestock or food animal, or a laboratory animal. All such uses arecontemplated as being within the scope of the invention. As used herein,a “patient” is an animal. In one embodiment, the animal is a bird,including but not limited to a chicken, turkey, duck, goose or quail, ora mammal. In another embodiment, the animal is a mammal, including butnot limited to a cow, horse, sheep, goat, pig, cat, dog, mouse, rat,hamster, rabbit, guinea pig, monkey and a human. In another embodiment,the animal is a primate or a human. In another embodiment, the animal isa human.

In one embodiment, structural materials for the inventive porouselastomers are synthetic polymers, especially but not exclusively,elastomeric polymers that are partially susceptible to biologicaldegradation, for example, in one embodiment, polycaprolactonepolyurethanes, polycaprolactone urea-urethanes,polycaprolactone-polylactide polyurethanes, polycaprolactone-polylactideurea-urethanes, polycaprolactone-polyglycolide polyurethanes,polycaprolactone-polyglycolide urea-urethanes, polycaprolactone-d/llactide polyurethanes, polycaprolactone-d/l lactide urea-urethanes,polycaprolactone-polyparadioxanone polyurethanes,polycaprolactone-polyparadioxanone urea-urethane or copolymers ormixtures thereofs. Some illustrative copolymers include but not limitedto polycaprolactone-co-glycolide-co-lactide polyurethanes,polycaprolactone-co-glycolide-co-lactide urea-urethanes,polycaprolactone-co-glycolide-co-d/l lactide polyurethanes,polycaprolactone-co-glycolide-co-d/l lactide urea-urethanes. Suchelastomers are generally hydrophobic but, pursuant to the invention, maybe treated to have surfaces that are less hydrophobic or somewhathydrophilic. In another embodiment, such elastomers may be produced withsurfaces that are significantly or largely hydrophobic

The reticulated at least partially degradable elastomeric products ofthe invention can be described as having a “macrostructure” and a“microstructure”, which terms are used herein in the general sensesdescribed in the following paragraphs.

The “macrostructure” refers to the overall physical characteristics ofan article or object formed of the at least partially degradableelastomeric product of the invention, such as: the outer periphery asdescribed by the geometric limits of the article or object, ignoring thepores or voids; the “macrostructural surface area” which references theoutermost surface areas as though any pores thereon were filled,ignoring the surface areas within the pores; the “macrostructuralvolume” or simply the “volume” occupied by the article or object whichis the volume bounded by the macrostructural, or simply “macro”, surfacearea; and the “bulk density” which is the weight per unit volume of thearticle or object itself as distinct from the density of the structuralmaterial.

The “microstructure” refers to the features of the interior structure ofthe at least partially degradable elastomeric material from which theinventive products are constituted such as pore dimensions; pore surfacearea, being the total area of the material surfaces in the pores; andthe configuration of the struts and intersections that constitute thesolid structure of certain embodiments of the inventive elastomericproduct.

Referring to FIG. 1, what is shown for convenience is a schematicdepiction of the particular morphology of a reticulated foam. FIG. 1 isa convenient way of illustrating some of the features and principles ofthe microstructure of embodiments of the invention. FIG. 1 is notintended to be an idealized depiction of an embodiment of, nor is it adetailed rendering of a particular embodiment of the elastomericproducts of the invention. Other features and principles of themicrostructure will be apparent from the present specification, or willbe apparent from one or more of the inventive processes formanufacturing porous elastomeric products that are described herein.

UMorphology

Described generally, the microstructure of the illustrated porous atleast partially degradable elastomeric matrix 10, which may, inter alia,be an individual element having a distinct shape or an extended,continuous or amorphous entity, comprises a reticulated solid phase 12formed of a suitable at least partially degradable elastomeric materialand interspersed therewithin, or defined thereby, a continuousinterconnected void phase 14, the latter being a principle feature of areticulated structure. In one embodiment, the reticulated structurecomprises a continuous, interconnected and intercommunicating networksof cells, pores, and voids to permit ingrowth and proliferation oftissue into the matrix interiors. In another embodiment, the void spaceof the reticulated structure comprises a plurality of interconnectedpores forming a continuous network of intercommunicating passagewaysextending from an interior portion to an exterior surface of saidmatrix.

In one embodiment, the elastomeric material of which elastomeric matrix10 is constituted may be a mixture or blend of multiple materials. Inanother embodiment, the elastomeric material is a single syntheticpolymeric elastomer such as will be described in more detail below. Inother embodiments, although elastomeric matrix 10 is subjected topost-reticulation processing, such as annealing, compressive moldingand/or reinforcement, it is to be understood that the elastomeric matrix10 retains its defining characteristics, that is, it remains at leastpartially degradable, reticulated and elastomeric.

Void phase 14 will usually be air- or gas-filled prior to use. Duringuse, void phase 14 can in many but not all cases become filled withliquid, for example, with biological fluids or body fluids.

Solid phase 12 of elastomeric matrix 10, as shown in FIG. 1, has anorganic structure and comprises a multiplicity of relatively thin struts16 that extend between and interconnect a number of intersections 18.The intersections 18 are substantial structural locations where three ormore struts 16 meet one another. Four or five or more struts 16 may beseen to meet at an intersection 18 or at a location where twointersections 18 can be seen to merge into one another. In oneembodiment, struts 16 extend in a three-dimensional manner betweenintersections 18 above and below the plane of the paper, favoring noparticular plane. Thus, any given strut 16 may extend from anintersection 18 in any direction relative to other struts 16 that joinat that intersection 18. Struts 16 and intersections 18 may havegenerally curved shapes and define between them a multitude of pores 20or interstitial spaces in solid phase 12. Struts 16 and intersections 18form an interconnected, continuous solid phase.

As illustrated in FIG. 1, the structural components of the solid phase12 of elastomeric matrix 10, namely struts 16 and intersections 18, mayappear to have a somewhat laminar configuration as though some were cutfrom a single sheet, it will be understood that this appearance may inpart be attributed to the difficulties of representing complexthree-dimensional structures in a two dimensional figure. Struts 16 andintersections 18 may have, and in many cases will have, non-laminarshapes including circular, elliptical and non-circular cross-sectionalshapes and cross sections that may vary in area along the particularstructure, for example, they may taper to smaller and/or larger crosssections while traversing along their longest dimension.

The cells of elastomeric matrix 10 are formed from clusters or groups ofpores 20, which would form the walls of a cell except that the cellwalls 22 of most of the pores 20 are absent or substantially absentowing to reticulation. In particular, a small number of pores 20 mayhave a cell wall of structural material also called a “window” or“window pane” such as cell wall 22. Such cell walls are undesirable tothe extent that they obstruct the passage of fluid and/or propagationand proliferation of tissues through pores 20. Cell walls 22 may, in oneembodiment, be removed in a suitable process step, such as reticulationas discussed below.

The individual cells forming the reticulated elastomeric matrix arecharacterized by their average cell diameter or, for nonspherical cells,by their largest transverse dimension. The reticulated elastomericmatrix comprises a network of cells that form a three-dimensionalspatial structure or void phase 14 which is interconnected via the openpores 20 therein. In one embodiment, the cells form a 3-dimensionalsuperstructure. The boundaries of individual cells can be visualizedfrom the sectioned struts 16 and/or intersections 18. The pores 20 aregenerally two- or three-dimensional structures. The pores provideconnectivity between the individual cells, or between clusters or groupsof pores which form a cell.

Except for boundary terminations at the macrostructural surface, in theembodiment shown in FIG. 1 solid phase 12 of elastomeric matrix 10comprises few, if any, free-ended, dead-ended or projecting “strut-like”structures extending from struts 16 or intersections 18 but notconnected to another strut or intersection.

However, in an alternative embodiment, solid phase 12 can be providedwith a plurality of such fibrils (not shown), e.g., from about 1 toabout 5 fibrils per strut 16 or intersection 18. In some applications,such fibrils may be useful, for example, for the additional surface areathey provide.

Struts 16 and intersections 18 can be considered to define the shape andconfiguration of the pores 20 that make up void phase 14 (or viceversa). Many of pores 20, in so far as they may be discretelyidentified, open into and communicate, by the at least partial absenceof cell walls 22, with at least two other pores 20. At intersections 18,three or more pores 20 may be considered to meet and intercommunicate.In certain embodiments, void phase 14 is continuous or substantiallycontinuous throughout elastomeric matrix 10, meaning that there are fewif any closed cell pores. Such closed cell pores, the interior volume ofeach of which has no communication with any other cell, e.g., isisolated from an adjacent cells by cell walls 22, represent loss ofuseful volume and may obstruct access of useful fluids to interior strutand intersection structures 16 and 18 of elastomeric matrix 10.

In one embodiment, closed cell pores, if present, comprise less thanabout 60% of the volume of elastomeric matrix 10. In another embodiment,closed cell pores, if present, comprise less than about 50% of thevolume of elastomeric matrix 10. In another embodiment, closed cellpores, if present, comprise less than about 40% of the volume ofelastomeric matrix 10. In another embodiment, closed cell pores, ifpresent, comprise less than about 50% of the volume of elastomericmatrix 10. In another embodiment, closed cell pores, if present,comprise less than about 30% of the volume of elastomeric matrix 10. Inanother embodiment, closed cell pores, if present, comprise less thanabout 25% of the volume of elastomeric matrix 10. In another embodiment,closed cell pores, if present, comprise less than about 20% of thevolume of elastomeric matrix 10. In another embodiment, closed cellpores, if present, comprise less than about 15% of the volume ofelastomeric matrix 10. In another embodiment, closed cell pores, ifpresent, comprise less than about 10% of the volume of elastomericmatrix 10. In another embodiment, closed cell pores, if present,comprise less than about 5% of the volume of elastomeric matrix 10. Inanother embodiment, closed cell pores, if present, comprise less thanabout 2% of the volume of elastomeric matrix 10. The presence of closedcell pores can be noted by their influence in reducing the volumetricflow rate of a fluid through elastomeric matrix 10 and/or as a reductionin cellular ingrowth and proliferation into elastomeric matrix 10.

In another embodiment, elastomeric matrix 10 is reticulated. In anotherembodiment, elastomeric matrix 10 is partially reticulated. In anotherembodiment, elastomeric matrix 10 is substantially reticulated. Inanother embodiment, elastomeric matrix 10 is fully reticulated. Inanother embodiment, elastomeric matrix 10 has many cell walls 22removed. In another embodiment, elastomeric matrix 10 has most cellwalls 22 removed. In another embodiment, elastomeric matrix 10 hassubstantially all cell walls 22 removed. In another embodiment,elastomeric matrix 10 has all cell walls 22 removed

In another embodiment, solid phase 12, which may be described asreticulated, comprises a continuous network of solid structures, such asstruts 16 and intersections 18, without any significant terminations,isolated zones or discontinuities, other than at the boundaries of theelastomeric matrix, in which network a hypothetical line may be tracedentirely through the material of solid phase 12 from one point in thenetwork to any other point in the network. The inventive implantabledevice, is reticulated, i.e., comprises an interconnected network ofcells and pores and channels and voids that provides fluid permeabilitythroughout the implantable device and permits cellular and tissueingrowth and proliferation into the interior of the implantable device.In one embodiment, the inventive implantable device, preferably theouter surface, is reticulated. The biodurable elastomeric matrix ormaterial is considered to be reticulated because its microstructure orthe interior structure comprises inter-connected and inter-communicatingpores and/or voids bounded by configuration of the struts andintersections that constitute the solid structure. The continuousinterconnected void phase is the principle feature of a reticulatedstructure.

In another embodiment, void phase 14 is also a continuous network ofinterstitial spaces, or intercommunicating fluid passageways for gasesor liquids, which fluid passageways extend throughout and are defined by(or define) the structure of solid phase 12 of elastomeric matrix 10 andopen into all its exterior surfaces. In another embodiment, void phase14 of elastomeric matrix 10 is continuous and fully accessible byproliferating tissues and cells or by fluids and interconnected andinter-communicating. In another embodiment, void phase 14 of elastomericmatrix 10 is a continuous interconnected and inter-communicating networkof voids, cells and pores and this continuous void phase is theprinciple characteristic of the reticulated matrix. In otherembodiments, as described above, there are only a few, substantially no,or no occlusions or closed cell pores that do not communicate with atleast one other pore 20 in the void network. Also in this void phasenetwork, a hypothetical line may be traced entirely through void phase14 from one point in the network to any other point in the network.

In concert with the objectives of the invention, in one embodiment themicrostructure of elastomeric matrix 10 can constructed to permit orencourage cellular adhesion to the surfaces of solid phase 12, neointimaformation thereon and cellular and tissue ingrowth and proliferationinto pores 20 of void phase 14, when elastomeric matrix 10 resides insuitable in vivo locations for a period of time. Owing to its partiallydegradable nature of elastomeric matrix 10, the cellular and tissueingrowth and proliferation into pores of the void phase is allowed toprogressively increased over time. In another embodiment, owing to itspartially degradable nature of elastomeric matrix 10, the amount ofcellular and tissue ingrowth and proliferation into pores of the voidphase progressively can increase over time as more void space is createdby the absorption of the partially degrading matrix.

In another embodiment, the reticulated structure allows for ingrowth forsuch tissues as fibrovascular tissues, fibroblasts, fibrocartilagecells, endothelial tissues, etc. In another embodiment, the tissueingrowth and proliferation into the interior of the implantable devicecan allow for bio-integration of the device to the site where the deviceis placed. In yet another embodiment, the tissue ingrowth andproliferation into the interior of the implantable device preventsmigration and recanalization.

Preferred scaffold materials for the implants have a reticulatedstructure with sufficient and required liquid permeability and thusselected to permit blood, or other appropriate bodily fluid, and cellsand tissues to access interior surfaces of the implants. This can happendue to the presence of inter-connected and inter-communicating,reticulated open pores and/or voids and/or channels and/or concavitiesthat form fluid passageways or fluid permeability providing fluid accessall through. These inter-connected and inter-communicating, reticulatedopen pores and/or cells and/or voids and/or channels and/or concavitiesare accessible for fluid passageways or fluid permeability providingfluid access all through. The accessible and inter-connected andinter-communicating nature of the reticulated matrix distinguishes itfrom porous materials and in porous materials although there are voids,not all of them are accessible as they are not all inter-communicatingand inter-connected as is the case with reticulated matrix. Over time,the tissue ingrowth and proliferation into the interior of theimplantable device placed at the defect site can lead to bio-integrationof the device to the site where the device is placed. Without beingbound by any particular theory, it is believed that the high voidcontent and degree of reticulation of the reticulated elastomeric matrixnot only allows for tissue ingrowth and proliferation of cells withinthe matrix but also allows for orientation and remodeling of the healedtissue after the initial tissues have grown into the implantable device.The biodurable reticulated elastomeric material that comprises theimplant device can allow for tissue ingrowth and proliferation andbio-integrate the implant device to the aneurysm site. The biodurablereticulated elastomeric material that comprises the implant device canallow for tissue ingrowth and will seal the aneurysm and in oneembodiment can provide a permanent sealing of the defect. Thereticulated elastomeric matrix and/or the implantable device, over time,provides functionality or substantial functionality such as load bearingcapability or re-modeling of of the initial cell and tissue infiltrationto the the morphology and structure similar to the original tissue thatis being repaired or replaced. Without being bound by any particulartheory, it is believed that owing to the high void content of thereticulated elastomeric matrix or implantable device comprising it, oncethe tissue is healed and bio-integration takes place, most of theregenerated or repaired site consists of new tissue and a small volumefraction of the reticulated elastomeric matrix, or the implantabledevice formed from it.

In another embodiment, such cellular or tissue ingrowth andproliferation, which may for some purposes include fibrosis and eventualtissue regeneration and re-modeling, can occur or be encouraged not justinto exterior layers of pores 20, but into the deepest interior of andthroughout elastomeric matrix 10. This is possible owing to the presenceof interconnected and inter-communicating cells and pores and voids, allof which are accessible for cellular or tissue ingrowth andproliferation. Thus, in this embodiment, the space occupied byelastomeric matrix 10 can become entirely filled by the cellular andtissue ingrowth and proliferation in the form of fibrotic, scar or othertissue except for the space occupied by the elastomeric solid phase 12.Over time as more void space is created by the absorption of thepartially degrading elastomeric solid phase, the additional void phaseis also filled by the cellular and tissue ingrowth and proliferation inthe form of fibrotic, scar or other tissue. In another embodiment, theinventive implantable device can function so that ingrown tissue is keptvital, for example, by the prolonged presence of a supportivemicrovasculature that is at least partially non-degradable.

To this end, particularly with regard to the morphology of void phase14, in one embodiment elastomeric matrix 10 is reticulated with openinterconnected and inter-communicating pores and these interconnectedand inter-communicating pores and voids are also accessible for cellularand tissue ingrowth and proliferation. Without being bound by anyparticular theory, this is thought to permit natural irrigation of theinterior of elastomeric matrix 10 with bodily fluids, e.g., blood, evenafter a cellular population has become resident in the interior ofelastomeric matrix 10 so as to sustain that population by supplyingnutrients thereto and removing waste products and degradation productstherefrom. In another embodiment, elastomeric matrix 10 is reticulatedwith open interconnected and inter-communicating pores pores of aparticular size range. In another embodiment, the interconnected andinter-communicating pores and voids facilitate and/or allow for theremoval of the degradation products as the implantable device or thereticulated matrix degrades, bio-degrades or bioabsorbs and in anotherembodiment, this removal happens during or in concert with the naturalirrigation by bodily fluids to and fro the interiors of elastomericmatrix 10, In another embodiment, elastomeric matrix 10 is reticulatedwith open interconnected pores with a distribution of size ranges. Inanother embodiment, elastomeric matrix 10 is reticulated withinterconnected and inter-communicating cell and pores and voids, all ofwhich are accessible by bodily fluids and cells and tissues.

It is intended that the various physical and chemical parameters ofelastomeric matrix 10 including in particular the parameters to bedescribed below, be selected to encourage cellular ingrowth andproliferation and also tissue ingrowth and proliferation according tothe particular application for which an elastomeric matrix 10 isintended.

It will be understood that such constructions of elastomeric matrix 10that provide interior cellular irrigation will be fluid permeable andmay also provide fluid access through and to the interior of the matrixfor purposes other than cellular irrigation, for example, for elution ofpharmaceutically-active agents, e.g., a drug such as nitric oxidereleasing polymer, anti-microbial agent platelet rich plasma or otherbiologically useful materials. Such materials may optionally be securedto the interior surfaces of elastomeric matrix 10 by application ofsuitable coatings that are preferably degradable and more preferablymade from degradable polymers.

In another embodiment of the invention, gaseous phase 12 can be filledor contacted with a deliverable treatment gas, for example, a sterilantsuch as ozone or a wound healant such as nitric oxide, provided that themacrostructural surfaces are sealed, for example by a bioabsorbablemembrane to contain the gas within the implanted product until themembrane erodes releasing the gas to provide a local therapeutic orother effect.

The matrix after its manufacture, which consists primarily of foaming,reticulation or machining to the desired size and shape of theimplantable device, is washed in organic solvent such as isopropylalcohol (IPA) and this removes any un-reacted ingredients and bringingdown the residual level of extractable of volatile and semi-volatileorganic compounds. The IPA wash is carried out by sonication in IPA forless than 30 minutes preferably less than 15 minutes and washing orcleaning by tumbling for times in excess of 2 hours or in excess of 4hours or in excess of 6 hours before removing the IPA by vacuum dying.The reticulated structure facilitates easier removal of residual unusedprocessing aids and/or unreacted starting ingredients during subsequentwash cycles, due to the presence of accessible open passages offered byinterconnected and intercommunicating network of cells and pores. Thewashed reticulated matrix is thus rendered more biocompatible withextractable levels below 50 ppm or in one embodiment, below 300 ppm orin another embodiment below 1000 ppm.

Useful embodiments of the invention include structures that are somewhatrandomized, as shown in FIG. 1 where the shapes and sizes of struts 16,intersections 18 and pores 20 vary substantially, and more orderedstructures which also exhibit the described features ofthree-dimensional interpenetration of solid and void phases, structuralcomplexity and high fluid permeability. The shapes and sizes of struts16, intersections 18 and pores 20 will eventually undergo more changesas the degradable part of the device or the product absorbs in abiocompatible fashion over a period of time. Such more orderedstructures can be produced by the processes of the invention as will befurther described below.

UPorosity

Post-reticulation, void phase 14 may comprise as little as 10% by volumeof elastomeric matrix 10, referring to the volume provided by theinterstitial spaces of elastomeric matrix 10 before any optionalinterior pore surface coating or layering is applied, such as for areticulated elastomeric matrix that, after reticulation, has beencompressively molded and/or reinforced as described in detail herein. Inanother embodiment, void phase 14 may comprise as little as 40% byvolume of elastomeric matrix 10. In another embodiment, void phase 14may comprise as little as 50% by volume of elastomeric matrix 10. Inanother embodiment, void phase 14 may comprise as least 70% by volume ofelastomeric matrix 10. In another embodiment, void phase 14 may compriseat least 95% by volume of elastomeric matrix 10. In one embodiment, thevolume of void phase 14, as just defined, is from about 10% to about 99%of the volume of elastomeric matrix 10. In another embodiment, thevolume of void phase 14, as just defined, is from about 40% to about 99%of the volume of elastomeric matrix 10. In another embodiment, thevolume of void phase 14, as just defined, is from about 30% to about 98%of the volume of elastomeric matrix 10. In another embodiment, thevolume of void phase 14, as just defined, is from about 50% to about 99%of the volume of elastomeric matrix 10. In another embodiment, thevolume of void phase 14, as just defined, is from about 70% to about 99%of the volume of elastomeric matrix 10. In another embodiment, thevolume of void phase 14 is from about 80% to about 98% of the volume ofelastomeric matrix 10. In another embodiment, the volume of void phase14 is from about 90% to about 98% of the volume of elastomeric matrix10.

One implanted in humans or animals or in in vivo situation, the voidphase or the accessible space for tissue and cell ingrowth andproliferation in the reticulated matrix progressively increases overtime owing to the partial or fully degradable nature of elastomericmatrix 10 that absorbs in a biocompatible fashion over a period of time.However in the case of least partially degradable reticulated matrix thepresence of the stable non-degradable part of the elastomeric matrix ordevice or products, does not allow for increase in void phase beyond acertain limit. The increase in void phase as elastomeric matrix 10 thatat least partially absorbs in a biocompatible fashion over a period oftime can be between 40% to 90%. In another embodiment, the increase invoid phase as elastomeric matrix 10 that at least partially absorbs in abiocompatible fashion over a period of time can be between 50% and 80 Inyet another embodiment, the increase in void phase as elastomeric matrix10 that at least partially absorbs in a biocompatible fashion over aperiod of time can be between 62% and 80%. In another embodiment, theincrease in void phase as elastomeric matrix 10 that at least partiallyabsorbs in a biocompatible fashion over a period of time can be greaterthan 95%. %. In another embodiment, the increase in void phase aselastomeric matrix 10 that at least partially absorbs in a biocompatiblefashion over a period of time can be between 10% and 50% and in anotherembodiment can be between 15% and 40%. In another embodiment, thepresence of a fully degradable elastomeric matrix or device or products,will allow for the void phase to increase with time until theelastomeric matrix is completely absorbed or degrades and the repaired,healed and re-modeled in-grown tissue will completely or substantiallycompletely fill the target site or the space occupied by the implantafter delivery and placement.

As used herein, when a pore is spherical or substantially spherical, itslargest transverse dimension is equivalent to the diameter of the pore.When a pore is non-spherical, for example, ellipsoidal or tetrahedral,its largest transverse dimension is equivalent to the greatest distancewithin the pore from one pore surface to another, e.g., the major axislength for an ellipsoidal pore or the length of the longest side for atetrahedral pore. As used herein, the “average diameter or other largesttransverse dimension” refers to the number average diameter, forspherical or substantially spherical pores, or to the number averagelargest transverse dimension, for non-spherical pores.

In one embodiment to encourage cellular ingrowth and proliferation andto provide adequate fluid permeability, the average diameter or otherlargest transverse dimension of pores 20 is at least about 10 μm. Inanother embodiment, the average diameter or other largest transversedimension of pores 20 is at least about 20 μm. In another embodiment,the average diameter or other largest transverse dimension of pores 20is at least about 50 μm. In another embodiment, the average diameter orother largest transverse dimension of pores 20 is at least about 100 μm.In another embodiment, the average diameter or other largest transversedimension of pores 20 is at least about 150 μm. In another embodiment,the average diameter or other largest transverse dimension of pores 20is at least about 250 μm. In another embodiment, the average diameter orother largest transverse dimension of pores 20 is greater than about 250μm. In another embodiment, the average diameter or other largesttransverse dimension of pores 20 is greater than 250 μm. In anotherembodiment, the average diameter or other largest transverse dimensionof pores 20 is at least about 450 μm. In another embodiment, the averagediameter or other largest transverse dimension of pores 20 is greaterthan about 450 μm. In another embodiment, the average diameter or otherlargest transverse dimension of pores 20 is greater than 450 μm. Inanother embodiment, the average diameter or other largest transversedimension of pores 20 is at least about 500 μm.

In another embodiment the average diameter or other largest transversedimension of pores 20 is not greater than about 800 μm. In anotherembodiment the average diameter or other largest transverse dimension ofpores 20 is not greater than about 600 μm. In another embodiment, theaverage diameter or other largest transverse dimension of pores 20 isnot greater than about 500 μm. In another embodiment, the averagediameter or other largest transverse dimension of pores 20 is notgreater than about 450 μm. In another embodiment, the average diameteror other largest transverse dimension of pores 20 is not greater thanabout 350 μm. In another embodiment, the average diameter or otherlargest transverse dimension of pores 20 is not greater than about 250μm. In another embodiment, the average diameter or other largesttransverse dimension of pores 20 is not greater than about 150 μm. Inanother embodiment, the average diameter or other largest transversedimension of pores 20 is not greater than about 20 μm.

In another embodiment, the average diameter or other largest transversedimension of pores 20 is from about 10 μm to about 50 μm. In anotherembodiment, the average diameter or other largest transverse dimensionof pores 20 is from about 20 μm to about 150 μm. In another embodiment,the average diameter or other largest transverse dimension of pores 20is from about 150 μm to about 250 μm. In another embodiment, the averagediameter or other largest transverse dimension of pores 20 is from about250 μm to about 500 μm. In another embodiment, the average diameter orother largest transverse dimension of pores 20 is from about 450 μm toabout 600 μm. In another embodiment, the average diameter or otherlargest transverse dimension of pores 20 is from about 10 μm to about500 μm. In another embodiment, the average diameter or other largesttransverse dimension of pores 20 is from about 20 μm to about 600 μm. Inanother embodiment, the average diameter or other largest transversedimension of pores 20 is from about 50 μm to about 600 μm. In anotherembodiment, the average diameter or other largest transverse dimensionof pores 20 is from about 100 μm to about 500 μm. In another embodiment,the average diameter or other largest transverse dimension of pores 20is from about 150 μm to about 350 μm.

In one embodiment to encourage cellular ingrowth and proliferation andto provide adequate fluid permeability, the average diameter or otherlargest transverse dimension of the cells of elastomeric matrix 10 is atleast about 100 μm. In another embodiment, the average diameter or otherlargest transverse dimension of it cells is at least about 150 μm. Inanother embodiment, the average diameter or other largest transversedimension of it cells is at least about 200 μm. In another embodiment,the average diameter or other largest transverse dimension of it cellsis at least about 250 μm.

In another embodiment, the average diameter or other largest transversedimension of the cells of elastomeric matrix 10 is not greater thanabout 1000 μm. In another embodiment, the average diameter or otherlargest transverse dimension of its cells is not greater than about 850μm. In another embodiment, the average diameter or other largesttransverse dimension of its cells is not greater than about 450 μm. Inanother embodiment, the average diameter or other largest transversedimension of its cells is not greater than about 700 μm. In anotherembodiment, the average diameter or other largest transverse dimensionof its cells is not greater than about 650 μm.

In another embodiment, the average diameter or other largest transversedimension of the cells of elastomeric matrix 10 is from about 100 μm toabout 1000 μm. In another embodiment, the average diameter or otherlargest transverse dimension of its cells is from about 150 μm to about850 μm. In another embodiment, the average diameter or other largesttransverse dimension of its cells is from about 200 μm to about 700 μm.In another embodiment, the average diameter or other largest transversedimension of its cells is from about 250 μm to about 650 μm.

In another embodiment, an implantable device made from elastomericmatrix 10 may comprise pore sizes that vary from small, e.g., 20 μm, tolarge, e.g., 500 μm, in a single device. In another embodiment, animplantable device made from elastomeric matrix 10 may comprise cellsizes that vary from small, e.g., 100 μm, to large, e.g., 1000 μm, in asingle device. In another embodiment, such a variation may occur acrossthe cross-section of the entire material or across any sub-section of across-section. In another embodiment, such a variation occurs in asystematic gradual transition. In another embodiment, such a variationoccurs in a stepwise manner. For example, the pore size distribution canbe from about 20 μm to about 70 μm on one end of an implantable deviceand be from about 300 μm to about 500 μm on another end of the device.This change in pore size distribution can take place in one or morecontinuous transitions or in one or more discrete steps. Such variationsin pore size distribution result in continuous transition zones or indiscrete steps, i.e., the transition from one pore size distribution toanother may be more gradual in the case of a continuous transition ortransitions but more distinct in the case of a discrete step or steps.With regard to pore orientation, similar transitions may occur in theorientation of the pores, with more oriented pores transitioning intoless oriented pores or even into pores substantially devoid oforientation across the cross-section or across a sub-section of thecross-section. The difference in the pore size distribution and/ororientation of the pores across a cross-section of implantable devicesmade from elastomeric matrix 10 may allow the device to be engineeredfor preferential behavior in terms of cell type, cell attachment, cellingrowth and/or cell proliferation. Alternatively, different pore sizedistribution and/or orientation of the pores across the cross-section ofimplantable devices made from elastomeric matrix 10 may allow the deviceto be engineered for preferential behavior in terms of tissue type,tissue attachment, tissue ingrowth and/or tissue proliferation.

The partially degradable reticulated or the fully degradable matrixinitially functions as a long term implantable pseudo-extracellularmatrix supporting the continuum of biological events through the healingand remodeling cascade. This biocompatible degradable reticulated or thefully degradable matrix induces eventual bio-integration by being i)receptive of cell membrane adhesion, ii) providing platelet adhesion,activation, aggregation, iii) allowing for angiogenesis (formation ofnew blood vessel) and granulation, iv) allowing for cell migration andproliferation and finally v) for the formation of the extra cellularmatrix synthesis (protein synthesis and assembly) and re-modeling of thesynthesized extra cellular matrix.

Cells are allowed to adhere, proliferate and differentiate along andthrough the contours of the structure formed by the pore sizedistribution. The cell orientation and cell morphology can be used toresult in engineered or newly-formed tissue that may further re-model tosubstantially replicate or mimic the anatomical features of realtissues, e.g., of the tissues being replaced. This preferential cellmorphology and orientation ascribed to the continuous or step-wise poresize distribution variations, with or without pore orientation, canoccur when the implantable device is placed, without prior cell seeding,into the tissue repair and regeneration site. This preferential cellmorphology and orientation ascribed to the continuous or step-wise poresize distribution can also occur when the implantable device is placedinto a patient, e.g., human or animal, tissue repair and regenerationsite after being subjected to in vitro cell culturing. These continuousor step-wise pore size distribution variations, with or without poreorientation, can be important characteristics for TE scaffolds in anumber of orthopedic applications, especially in soft tissue attachment,repair, regeneration, augmentation and/or support encompassing thespine, shoulder, knee, hand or joints, and in the growth of a prostheticorgan. In another embodiment, these continuous or step-wise pore sizedistribution variations, with or without pore orientation, can beimportant characteristics for TE scaffolds in a number of other surgicalapplications such as wound healing and defect filling, healing of tissuewhere weakness exists such as for repair of soft tissue defects,specifically inguinal, femoral, ventral, incisional, umbilical, andepigastric hernias; surgical meshes for tissue augmentation, support andrepair; for therapeutic purposes. In another embodiment, thesecontinuous or step-wise pore size distribution variations, with orwithout pore orientation, can be important characteristics for TEscaffolds in a number of applications healing of vascular andneuro-vascular defects including arteriovenous malformations (AVMs),aneurysms, anomalies of feeding and draining veins, arteriovenousfistulas, e.g., anomalies of large arteriovenous connections, andabdominal aortic aneurysm endograft endoleaks (e.g., inferior mesentericarteries and lumbar arteries associated with the development of Type IIendoleaks in endograft patients). In another embodiment, thesecontinuous or step-wise pore size distribution variations, with orwithout pore orientation, can be important characteristics for TEscaffolds in a number of applications for cosmetic, reconstructive,urologic or gastroesophageal, gynecological, pelvic prolapse repairpurposes. In another embodiment, these continuous or step-wise pore sizedistribution variations, with or without pore orientation, can beimportant characteristics for TE scaffolds in a number of applicationsfor in wound healing, chronic wound healing, pressure and diabetic soresand other dermal tissue regeneration.

The morphology or structure of interconnected and inter-communicatingnetwork of accessible cells and pores in the reticulated matrix is verydifferent from the porous structure formed by textile processing such asweaving, braiding and knitting and used to make grafts or graft jackets.The textile processes produce a more regular structure, do not have voidcontent as high as reticulated matrix and do not have a system ofinterconnected and inter-communicating network of pores. In general, thethree-dimensional form of structures made by textile processes have poresize that is on very rare occasions higher than 50 microns and the poresize of the reticulated elastomeric matrix is usually above 50 micronsand more likely above 100 microns. The pore size of the reticulatedelastomeric matrix, prior to thermal processing, compression molding,compressive molding or annealing is usually above 50 microns and morelikely above 100 microns. In another embodiment, the morphology orstructure of interconnected and inter-communicating network ofaccessible cells and pores in the reticulated matrix is very differentfrom the porous structure formed by lossscaffold/leaching/lyophilization techniques. The porosity is not as highfor scaffolds or structure made by scaffold/leaching/lyophilizationtechniques compared to reticulated matrix and the interconnectivity andaccessibility for those techniques is also lower than reticulatedmatrix. Even in cases where porosities can be high, they still do notpossess the high degree of interconnectivity between the cells and poresin the absence of a reticulation step. All the methods relating to lossscaffold/leaching/lyophilization techniques are made from thermoplasticpolymers high molecular weights and when they dissolve form liquids withhigh viscosities; the high viscosities makes it physically impossible toform and grow inter-connected void phase or interconnected pores andcells within his highly viscous fluid. On the other hand in case ofdegradable urethane matrix, the formation of the pores and cells occurssimultaneously with the polymerization reaction so the pores and voidsnucleate and grow in low viscosity and reticulation removes the cellmembranes and the windows to provide the inter-connected andinter-communicating structure The control of pore size,interconnectivity of pores and the accessibility of scaffolds orstructure made by lyophilization is lower than the reticulated matrix asis the mechanical properties of the scaffolds or structure made bylyophilization. Also the structures made by textile processes do notgenerally possess the same degree of elastomeric properties or are asresilient in recovery as reticulated elastomeric matrix. Other porousmatrix made by processes such as electro-static spinning producestructures that do not have the same degree of interconnected andinter-communicating network of accessible cells and pores as reticulatedelastomeric matrix usually have lower void fraction compared toreticulated matrix and have pore size that are usually below 50 micronsand in most cases below 30 microns. Also structures made byelectro-static spinning, loss scaffold/leaching/lyophilizationtechniques being usually made from polymers that are predominantlythermoplastic in nature, are less elastomeric and less resilient inrecovery compared to the reticulated elastomeric matrix. Also each ofthe foaming and reticulation processing steps take place in less than 10minutes or in less than 5 minutes; the processing steps to make porousstructure formed by loss scaffold/leaching/lyophilization techniquestake several hours and in sometimes days to accomplish.

Size and Shape

Elastomeric matrix 10 can be readily fabricated in any desired size andshape. It is a benefit of the invention that elastomeric matrix 10 issuitable for mass production from bulk stock by subdividing such bulkstock, e.g., by cutting, die punching, laser slicing, or compressionmolding. In one embodiment, subdividing the bulk stock can be done usinga heated surface. It is a further benefit of the invention that theshape and configuration of elastomeric matrix 10 may vary widely and canreadily be adapted to desired anatomical morphologies.

The size, shape, configuration and other related details of elastomericmatrix 10 can be either customized to a particular application orpatient or standardized for mass production. However, economicconsiderations may favor standardization. To this end, elastomericmatrix 10 or a composite mesh comprising reticulated elastomeric matrix10 can be embodied in a kit comprising elastomeric implantable devicepieces of different sizes and shapes. Also, as discussed elsewhere inthe present specification and as is disclosed in the applications towhich priority is claimed, multiple, e.g. two, three or four, individualelastomeric matrices 10 or composite mesh comprising reticulatedelastomeric matrix 10 can be used as an implantable device system for asingle target biological site, being sized or shaped or both sized andshaped to function cooperatively for treatment of an individual targetsite.

The practitioner performing the procedure, who may be a surgeon or othermedical or veterinary practitioner, researcher or the like, may thenchoose one or more implantable devices from the available range to usefor a specific treatment, for example, as is described in theapplications to which priority is claimed in U.S. Patent ApplicationPublication No. 2007/019108, the disclosures of which are incorporatedherein by this reference.

By way of example, the minimum dimension of elastomeric matrix 10 or acomposite mesh comprising reticulated elastomeric matrix 10 may be aslittle as 0.5 mm and the maximum dimension as much as 100 mm or evengreater. In another embodiment, the minimum dimension of elastomericmatrix 10 or composite mesh comprising reticulated elastomeric matrix 10may be as little as 0.5 mm and the maximum dimension as much as 200 mmor even greater. However, in one embodiment it is contemplated that anelastomeric matrix 10 or a composite mesh comprising reticulatedelastomeric matrix 10 of such dimension intended for implantation wouldhave an elongated shape, such as the shapes of cylinders, rods, tubes orelongated prismatic forms, or a folded, coiled, helical or other morecompact configuration. In another embodiment, it is contemplated that anelastomeric matrix 10 or composite mesh comprising reticulatedelastomeric matrix 10 of such dimension intended for implantation wouldhave a shape of a flat sheet or a long ribbon or a folded sheet withsquare or rectangular configuration. Comparably, a dimension as small as0.5 mm can be a transverse dimension of an elongated shape or of aribbon or sheet-like implantable device.

In an alternative embodiment, an elastomeric matrix 10 or a compositemesh comprising reticulated elastomeric matrix 10 having a spherical,cubical, tetrahedral, toroidal or other form having no dimensionsubstantially elongated when compared to any other dimension and with adiameter or other maximum dimension of from about 0.5 mm to about 500 mmmay have utility, for example, for an orthopedic application site, softtissue defect site such as various forms of hernias, other soft tissuedefect site for augmentation, support and ingrowth that require surgicalmeshes and wound healing sites and chronic wound healing sites Inanother embodiment, the elastomeric matrix 10 having such a form has adiameter or other maximum dimension from about 3 mm to about 20 mm.

For most implantable device applications, macrostructural sizes ofelastomeric matrix 10 or a composite mesh comprising reticulatedelastomeric matrix 10 include the following embodiments: compact shapessuch as spheres, cubes, pyramids, tetrahedrons, cones, cylinders,trapezoids, parallelepipeds, ellipsoids, fusiforms, tubes or sleeves,and many less regular shapes having transverse dimensions of from about1 mm to about 200 mm (In another embodiment, these transverse dimensionsare from about 5 mm to about 100 mm.); and sheet- or strip-like shapeshaving a thickness of from about 0.5 to about 20 mm (In anotherembodiment, these thickness are from about 1 to about 5 mm.) and lateraldimensions of from about 5 to about 200 mm (In another embodiment, theselateral dimensions are from about 10 to about 100 mm.).

The inventors have investigated the use of an implantable elastomericmatrix 10 for orthopedic, hernia, surgical mesh, wound healing, andchronic wound healing applications. It was discovered that the matrix ofthe present invention provides unexpected benefits suitable foraugmentation, support and ingrowth purposes. It is an advantage of theinvention that the implantable elastomeric matrix 10 elements orcomposite mesh comprising reticulated elastomeric matrix 10 can beeffectively employed without any need to closely conform to theconfiguration to the application site, which may often be complex anddifficult to model. Another unexpected advantage of the invention isthat the implantable elastomeric matrix elements or composite meshcomprising reticulated elastomeric matrix 10 embodiment is that whenoversized with respect to the soft tissue defect which can be fororthopedic or hernia repair or wound healing applications, theimplantable device conformally fits the tissue defect. Without beingbound by any particular theory, the resilience and recoverable behaviorthat leads to such a conformal fit results in the formation of a tightboundary between the walls of the implantable device and the defect withsubstantially no clearance, thereby providing an interface conducive tothe promotion of cellular ingrowth and tissue proliferation.

Furthermore, in one embodiment, the implantable device of the presentinvention; or implantable devices if more than one is used, should notcompletely fill the application site even when fully expanded in situ.In one embodiment, the fully expanded implantable device(s) of thepresent invention are smaller in a dimension than the application siteand provide sufficient space within the application site to ensurevascularization, cellular ingrowth and proliferation, and for possiblepassage of blood to the implantable device. In another embodiment, thefully expanded implantable device(s) of the present invention aresubstantially the same in a dimension as the application site. Inanother embodiment, the fully expanded implantable device(s) of thepresent invention are larger in a dimension than the application site.In another embodiment, the fully expanded implantable device(s) of thepresent invention are smaller in volume than the application site. Inanother embodiment, the fully expanded implantable device(s) of thepresent invention are substantially the same volume as the applicationsite. In another embodiment, the fully expanded implantable device(s) ofthe present invention are larger in volume than the application site.

In another embodiment, after being placed in the application site theexpanded implantable device(s) of the present invention does not swellsignificantly or appreciably. The reticulated matrix or the implantabledevice(s) of the present invention are not considered to be anexpansible material or a hydrogel or water swellable. The reticulatedmatrix is not considered to be a foam gel. The reticulated matrix doesnot expand swell on contact with bodily fluid or blood or water. In oneembodiment, the reticulated matrix does not substantially expand orswell on contact with bodily fluid or blood or water.

Some useful implantable device shapes may approximate the contour of aportion of the target application site and in one embodiment, theresilient nature of the reticulated matrix allows for larger or slightlylarger implantable device to compress appropriately in order toapproximate the contour of a portion of the target application site. Inone embodiment, the implantable device is shaped as relatively simpleconvex, dish-like or hemispherical or hemi-ellipsoidal shape orcylindrical and size that is appropriate for treating multiple differentsites in different patients.

It is contemplated, in another embodiment, upon implantation, beforetheir pores become filled with biological fluids, bodily fluids and/ortissue, such implantable devices for applications and the like do notentirely fill, cover or span the biological site in which they resideand that an individual implanted elastomeric matrix 10 or composite meshcomprising reticulated elastomeric matrix 10 will, in many casesalthough not necessarily, have at least one dimension of no more than50% of the biological site within the entrance thereto or over 50% ofthe damaged tissue that is being repaired or replaced. In anotherembodiment, an individual implanted elastomeric matrix 10 or compositemesh comprising reticulated elastomeric matrix 10 as described abovewill have at least one dimension of no more than 75% of the biologicalsite within the entrance thereto or over 75% of the damaged tissue thatis being repaired or replaced. In another embodiment, an individualimplanted elastomeric matrix 10 or composite mesh comprising reticulatedelastomeric matrix 10 as described above will have at least onedimension of no more than 95% of the biological site within the entrancethereto or over 95% of the damaged tissue that is being repaired orreplaced.

In another embodiment, upon implantation, before their pores becomefilled with biological fluids, bodily fluids and/or tissue, suchimplantable devices for applications and the like substantially fill,cover or span the biological site in which they reside and an individualimplanted elastomeric matrix 10 or composite mesh comprising reticulatedelastomeric matrix 10 will, in many cases, although not necessarily,have at least one dimension of no more than about 100% of the biologicalsite within the entrance thereto or cover 100% of the damaged tissuethat is being repaired or replaced. In another embodiment, an individualimplanted elastomeric matrix 10 or composite mesh comprising reticulatedelastomeric matrix 10 as described above will have at least onedimension of no more than about 98% of the biological site within theentrance thereto or cover 98% of the damaged tissue that is beingrepaired or replaced. In another embodiment, an individual implantedelastomeric matrix 10 or composite mesh comprising reticulatedelastomeric matrix 10 as described above will have at least onedimension of no more than about 102% of the biological site within theentrance thereto or cover 102% of the damaged tissue that is beingrepaired or replaced.

In another embodiment, upon implantation, before their pores becomefilled with biological fluids, bodily fluids and/or tissue, suchimplantable devices for applications such as soft tissue orthopedicdefect, soft tissue defect site such as various forms of hernias, othersoft tissue defect site for augmentation, support and ingrowth thatrequire surgical meshes and wound healing sites and the like over fill,cover or span the biological site in which they reside and an individualimplanted elastomeric matrix 10 or composite mesh comprising reticulatedelastomeric matrix 10 will, in many cases, although not necessarily,have at least one dimension of more than about 105% of the biologicalsite within the entrance thereto or cover 105% of the damaged tissuethat is being repaired or replaced. In another embodiment, an individualimplanted elastomeric matrix 10 as described above will have at leastone dimension of more than about 125% of the biological site within theentrance thereto or cover 125% of the damaged tissue that is beingrepaired or replaced. In another embodiment, an individual implantedelastomeric matrix 10 as described above will have at least onedimension of more than about 150% of the biological site within theentrance thereto or cover 150% of the damaged tissue that is beingrepaired or replaced. In another embodiment, an individual implantedelastomeric matrix 10 or composite mesh comprising reticulatedelastomeric matrix 10 as described above will have at least onedimension of more than about 200% of the biological site within theentrance thereto or cover 200% of the damaged tissue that is beingrepaired or replaced. In another embodiment, an individual implantedelastomeric matrix 10 or composite mesh comprising reticulatedelastomeric matrix 10 as described above will have at least onedimension of more than about 300% of the biological site within theentrance thereto or cover 300% of the damaged tissue that is beingrepaired or replaced.

One embodiment for use in the practice of the invention is a reticulatedelastomeric matrix 10 which is sufficiently flexible and resilient,i.e., resiliently-compressible, to enable it to be initially compressedunder ambient conditions, e.g., at 25° C., from a relaxed configurationto a first, compact configuration for delivery via a delivery-device,e.g., catheter, endoscope, syringe, cystoscope, trocar or other suitableintroducer instrument, for delivery in vitro and, thereafter, to expandto-a second, working configuration in situ. Furthermore, in anotherembodiment, an elastomeric matrix can have the herein describedresilient-compressibility after being compressed about 5-95% of anoriginal dimension (e.g., compressed about 19/20th- 1/20th of anoriginal dimension). In another embodiment, an elastomeric matrix canhave the herein described resilient-compressibility after beingcompressed about 10-90% of an original dimension (e.g., compressed about9/10th- 1/10th of an original dimension). As used herein, elastomericmatrix 10 can have “resilient-compressibility”, i.e., is“resiliently-compressible”, when the second, working configuration, invitro, is at least about 50% of the size of the relaxed configuration inat least one dimension. In another embodiment, theresilient-compressibility of elastomeric matrix 10 is such that thesecond, working configuration, in vitro, is at least about 80% of thesize of the relaxed configuration in at least one dimension. In anotherembodiment, the resilient-compressibility of elastomeric matrix 10 issuch that the second, working configuration, in vitro, is at least about90% of the size of the relaxed configuration in at least one dimension.In another embodiment, the resilient-compressibility of elastomericmatrix 10 is such that the second, working configuration, in vitro, isat least about 97% of the size of the relaxed configuration in at leastone dimension.

In another embodiment, an elastomeric matrix can have the hereindescribed resilient-compressibility after being compressed about 5-95%of its original volume (e.g., compressed about 19/20th- 1/20th of itsoriginal volume). In another embodiment, an elastomeric matrix can havethe herein described resilient-compressibility after being compressedabout 10-90% of its original volume (e.g., compressed about 9/10th-1/10th of its original volume). As used herein, “volume” is the volumeswept-out by the outermost 3-dimensional contour of the elastomericmatrix. In another embodiment, the resilient-compressibility ofelastomeric matrix 10 is such that the second, working configuration, invivo, is at least about 50% of the volume occupied by the relaxedconfiguration. In another embodiment, the resilient-compressibility ofelastomeric matrix 10 is such that the second, working configuration, invivo, is at least about 80% of the volume occupied by the relaxedconfiguration. In another embodiment, the resilient-compressibility ofelastomeric matrix 10 is such that the second, working configuration, invivo, is at least about 90% of the volume occupied by the relaxedconfiguration. In another embodiment, the resilient-compressibility ofelastomeric matrix 10 is such that the second, working configuration, invivo, occupies at least about 97% of the volume occupied by theelastomeric matrix in its relaxed configuration.

One embodiment for use in the practice of the invention is a reticulatedelastomeric matrix or a composite mesh comprising reticulatedelastomeric matrix which is sufficiently flexible and resilient, i.e.,resiliently-compressible, to enable it to be initially compressed underambient conditions, e.g., at 25° C., from a relaxed configuration to afirst, compact configuration for delivery via a delivery-device, e.g.,catheter, endoscope, syringe, cystoscope, trocar or other suitableintroducer instrument, for delivery in vitro and, thereafter, to expandto a second, working configuration in situ.

Elastomeric Matrix Physical Properties

A reticulated at least partially or fully degradable elastomeric matrix10, an implantable device comprising a reticulated elastomeric matrix,can have any suitable bulk density, also known as specific gravity,consistent with its other properties. In another embodiment, Elastomericmatrix 10, a reticulated at least partially or fully degradableelastomeric matrix, an implantable device comprising a reticulatedelastomeric matrix, and/or an implantable device comprising acompressive molded reticulated elastomeric matrix can have any suitablebulk density, also known as specific gravity, consistent with its otherproperties. For example, in one embodiment, the bulk density, asmeasured pursuant to the test method described in ASTM Standard D3574,may be from about 0.008 g/cc to about 0.96 g/cc (from about 0.50 lb/ft³to about 60 lb/ft³). In another embodiment, the bulk density may be fromabout 0.016 g/cc to about 0.56 g/cc (from about 1.0 lb/ft³ to about 35lb/ft). In another embodiment, the bulk density may be from about 0.008g/cc to about 0.15 g/cc (from about 0.50 lb/ft³ to about 9.4 lb/ft³). Inanother embodiment, the bulk density may be from about 0.008 g/cc toabout 0.127 g/cc (from about 0.5 lb/ft³ to about 8 lb/ft³). In anotherembodiment, the bulk density may be from about 0.008 g/cc to about 0.288g/cc (from about 0.5 lb/ft³ to about 18 lb/ft³). In another embodiment,the bulk density may be from about 0.016 g/cc to about 0.115 g/cc (fromabout 1.0 lb/ft³ to about 7.2 lb/ft³). In another embodiment, the bulkdensity may be from about 0.024 g/cc to about 0.104 g/cc (from about 1.5lb/ft³ to about 6.5 lb/ft³).

Elastomeric matrix 10 can have any suitable microscopic surface areaconsistent with its other properties. From an exposed plane of theporous material, one can estimate the microscopic surface area from thepore frequency, e.g., the number of pores per linear millimeter, and canroutinely estimate the pore frequency from the average cell sidediameter in μm.

Elastomeric Matrix Mechanical Properties

In one embodiment, at least partially degradable or fully degradablereticulated elastomeric matrix 10 can have sufficient structuralintegrity to be self-supporting and free-standing in vitro. However, inanother embodiment, elastomeric matrix 10 can be furnished withstructural supports such as ribs or struts or reinforcements.

The at least partially degradable or fully degradable reticulatedelastomeric matrix 10 has sufficient tensile strength such that it canwithstand normal manual or mechanical handling during its intendedapplication and during post-processing steps that may be required ordesired without tearing, breaking, crumbling, fragmenting or otherwisedisintegrating, shedding pieces or particles, or otherwise losing itsstructural integrity. The tensile strength of the starting material(s)should not be so high as to interfere with the fabrication or otherprocessing of elastomeric matrix 10.

Thus, for example, in one embodiment at least partially degradable orfully degradable reticulated elastomeric matrix 10 may have a tensilestrength of from about 7000 kg/m² to about 105,000 kg/m² (from about 10psi to about 150 psi). In another embodiment, elastomeric matrix 10 mayhave a tensile strength of from about 10,500 kg/m² to about 70,000 kg/m²(from about 15 psi to about 100 psi). In another embodiment, reticulatedelastomeric matrix 10 may have a tensile modulus of from about 7,000kg/m² to about 63,000 kg/m² (from about 10 psi to about 90 psi).

Sufficient ultimate tensile elongation is also desirable. For example,in another embodiment, at least partially degradable or fully degradablereticulated elastomeric matrix 10 can have an ultimate tensileelongation of at least about 75%. In another embodiment, elastomericmatrix 10 can have an ultimate tensile elongation of at least about125%. In another embodiment, elastomeric matrix 10 can have an ultimatetensile elongation of at least about 150%. In another embodiment,elastomeric matrix 10 can have an ultimate tensile elongation of atleast about 200%. In one embodiment, these high elongation to breakmakes these at least partially degradable or fully degradablereticulated matrix comprise elastomeric properties. In anotherembodiment, these high elongation to break coupled with low modulus makethese at least partially degradable or fully degradable reticulatedmatrix comprise elastomeric properties. The elastomeric nature of theseat least partially degradable or fully degradable reticulatedelastomeric matrix arises from their cross-linked structure which allowsfor high elongation to beak or high strain to failure.

In one embodiment, reticulated elastomeric matrix 10 may have acompressive modulus of from about 7,000 kg/m² to about 63,000 kg/m²(from about 10 psi to about 90 psi). In another embodiment, reticulatedelastomeric matrix 10 can have a compressive strength of from about 70kg/m² to about 350,00 kg/m² (from about 0.1 psi to about 50 psi) at 50%compression strain. In another embodiment, reticulated elastomericmatrix 10 can have a compressive strength of from about 140 kg/m² toabout 21,100 kg/m² (from about 0.2 psi to about 30 psi) at 50%compression strain.

In one embodiment, the elastomeric matrix 10 is allowed to expand fromthe first, compact configuration to the second, working configurationover a short time, e.g., about 90% recovery in 90 seconds or less in oneembodiment, or in 40 seconds or less in another embodiment, each from75% compression strain held for up to 10 minutes. In another embodiment,the expansion from the first, compact configuration to the second,working configuration can occur over a short time, e.g., about 95%recovery in 180 seconds or less in one embodiment, in 90 seconds or lessin another embodiment, in 60 seconds or less in another embodiment, eachfrom 75% compression strain held for up to 30 minutes. In anotherembodiment, elastomeric matrix 10 can recover in about 10 minutes tooccupy at least about 97% of the volume occupied by its relaxedconfiguration, following 75% compression strain held for up to 30minutes. In another embodiment, the expansion from the first, compactconfiguration to the second, working configuration can occur over ashort time, e.g., about 90% recovery in 180 seconds or less in oneembodiment, in 90 seconds or less in another embodiment, in 60 secondsor less in another embodiment, in 30 seconds or less in anotherembodiment, each from 50% compression strain held for up to 120 minutes.This recovery is due to the resilient nature of the at least partiallydegradable or fully degradable elastomeric matrix.

In another embodiment, reticulated elastomeric matrix 10 can have astatic recovery time, t-90%, following a 50% uniaxial compression andthen, while maintaining that uniaxial compression, can impart, in an airatmosphere, a dynamic loading off ±5% strain at a frequency of 1 Hz for5,000 cycles or 100,000 cycles. In another embodiment, reticulatedelastomeric matrix 10 can have a static recovery time, t-90%, of fromabout 100 sec. to about 2,000 sec. In another embodiment, reticulatedelastomeric matrix 10 can have a static recovery time, t-90%, of fromabout 125 sec. to about 1,500 sec. This dynamic recovery is due to theresilient nature of the at least partially degradable or fullydegradable elastomeric matrix

The mechanical properties of the porous materials described herein, ifnot indicated otherwise, may be determined according to ASTM D3574-01entitled “Standard Test Methods for Flexible Cellular Materials—Slab,Bonded and Molded Urethane Foams”, or other such method.

Furthermore, if porosity is to be imparted to the elastomer employed forelastomeric matrix 10 after rather than during the polymerizationreaction, good proccessability is also desirable for post-polymerizationshaping and fabrication. For example, in one embodiment, elastomericmatrix 10 can have low tackiness.

Elastomeric Matrices from Elastomer Polymerization, Cross-Linking andFoaming

In further embodiments, the invention provides a porous at leastpartially degradable elastomer or fully degradable elastomer and aprocess for polymerizing, cross-linking and foaming the same which canbe used to produce an at least partially degradable reticulatedelastomeric matrix 10 as described herein. In another embodiment,reticulation follows.

More particularly, in another embodiment, the invention provides aprocess for preparing an at least partially degradable elastomericpolyurethane matrix which comprises synthesizing the matrix from apolyol component comprising polycaprolactone or its copolymers and anisocyanate component by polymerization, cross-linking and foaming,thereby forming pores, followed by reticulation of the foam to provide areticulated product. In this embodiment, the product is designated as apolycaprolactone polyurethane, being a polymer comprising urethanegroups formed from, e.g., the hydroxyl groups of the polycaprolactonepolyol component and the isocyanate groups of the isocyanate component.In another embodiment, the product is designated as a polycaprolactoneurea-urethane, being a polymer comprising urethane groups formed from,e.g., the hydroxyl groups of the polycaprolactone polyol component andthe isocyanate groups of the isocyanate component and urea linkages orgroups formed from reaction of isocyanate component with water componentused for foaming. In this embodiment, the process employs controlledchemistry to provide a reticulated elastomer product with controlleddegradable characteristics that can be at least partially or fullydegradable. Pursuant to the invention, the polymerization can beconducted to provide a foam product employing chemistry that avoidsbiologically undesirable or nocuous constituents therein.

In one embodiment, as one starting material, the process employs atleast one polyol component. For the purposes of this application, theterm “polyol component” includes molecules comprising, on the average,about 2 hydroxyl groups per molecule, i.e., a difunctional polyol or adiol, as well as those molecules comprising, on the average, greaterthan about 2 hydroxyl groups per molecule, i.e., a polyol or amulti-functional polyol. Exemplary polyols can comprise, on the average,from about 2 to about 5 hydroxyl groups per molecule. In one embodiment,as one starting material, the process employs a difunctional polyolcomponent. In this embodiment, because the hydroxyl group functionalityof the diol is about 2, it does not provide the so-called “soft segment”with soft segment cross-linking In another embodiment, as one startingmaterial of the polyol component, the process employs a multi-functionalpolyol component in sufficient quantity to provide a controlled degreeof soft segment cross-linking. In another embodiment, the processprovides sufficient soft segment cross-linking to yield a stable foam.In another embodiment, the soft segment is composed of a polyolcomponent that is generally of a relatively low molecular weight, in oneembodiment from about 350 to about 6,000 Daltons, and from about 450 toabout 4,000 Daltons in another embodiment. In another embodiment, themolecular weight of the polyol component is from about 1000 to about3,000 Daltons. In another embodiment, the molecular weight of the polyolcomponent is from about 750 to about 3,500 Daltons. In anotherembodiment, the molecular weight of the polyol component is above about750 Daltons. Thus, these polyols are generally liquids orlow-melting-point solids. This soft segment polyol is terminated withhydroxyl groups, either primary or secondary. In another embodiment, asoft segment polyol component has about 2 hydroxyl groups per molecule.In another embodiment, a soft segment polyol component has greater thanabout 2 hydroxyl groups per molecule; more than 2 hydroxyl groups perpolyol molecule are required of some polyol molecules to impartsoft-segment cross-linking.

In one embodiment, the average number of hydroxyl groups per molecule inthe polyol component is about 2. In another embodiment, the averagenumber of hydroxyl groups per molecule in the polyol component isgreater than about 2. In another embodiment, the average number ofhydroxyl groups per molecule in the polyol component is greater than 2.In one embodiment, the polyol component comprises a tertiary carbonlinkage. In one embodiment, the polyol component comprises a pluralityof tertiary carbon linkages.

In one embodiment, the polyol component is a polycaprolactone polyol,polyester polyol, glycolide polyol, l-lactide polyol, d-l lactidepolyol, polyether polyol, polycarbonate polyol, hydrocarbon polyol,polysiloxane polyol, poly(ether-co-ester)polyol,poly(caprolactone-co-glycolide)polyol,poly(caprolactone-co-l-lactide)polyol,poly(caprolactone-co-d-l-lactide)polyol,poly(caprolactone-co-para-dioxanone)polyol,(caprolactone-co-l-lactide-co glycolide)polyol,poly(caprolactone-co-glycolide-co-d-l lactide)polyol,poly(caprolactone-co-carbonate)polyol,poly(caprolactone-co-siloxane)polyol; polyol,poly(caprolactone-co-hydrocarbon)polyol, polyethylene glycol polyol,polysaccharide polyol, or a mixture thereof. In another embodiment, thepolyol component comprises polycaprolactone polyol or copolymers ofpolycaprolactone. In another embodiment, the polyol component comprisespolycaprolactone or copolymers of polycaprolactone. The mole percentageof caprolactone in the copolymer polyol varies from 30% to 97%. Inanother embodiment, the mole percentage of caprolactone in the copolymerpolyol varies from 40% to 95%. In another embodiment, the molepercentage of caprolactone in the copolymer polyol varies from 60% to95%. In another embodiment, the mole percentage of caprolactone in thecopolymer polyol varies from 70% to 95%. In another embodiment, the molepercentage of caprolactone in the copolymer polyol varies from 80% to95%. If the poly caprolactone polyol is a solid at 25° C., it istypically melted prior to further processing.

The soft segment of the partially degradable and fully degradablereticulated elastomeric matrix comprises the polyol and will at leastpartially degrade or at least partially hydrolyze or at least partialabsorb or bioabsorb over time. In another embodiment, the soft segmentpart comprising polyol component will completely degrade or hydrolyze orabsorb or bioabsorb over time. In another embodiment, the polyolcomponent comprising polycaprolactone will completely degrade orhydrolyze or absorb or bioabsorb over time. The soft segment partcomprising polyol polyol component will degrade by hydrolysis and loseit mechanical properties or integrity over time. The degradation rateand time of the soft segment will depend on the composition of thesehydrolysable polyols. In one embodiment, it is expected that that forcopolymer polyols where the polycaprolactone is the major component andfor the same polycaprolactone content, polyols containing glycolide willdegrade fastest rate, polyols containing l-lactide will degrade at aslowest rate and polyol containing d-l-lactide will degrade at anintermediate rate. In one embodiment, it is expected that that forcopolymer polyols where the polycaprolactone is greater than or about 60mole % in the copolymer polyol, polyols containing glycolide willdegrade fastest rate, polyols containing l-lactide will degrade at aslowest rate and polyol containing d-l-lactide will degrade at anintermediate rate. In one embodiment, it is expected that that forcopolymer polyols where the polycaprolactone is greater than or about 70mole % in the copolymer polyol, polyols containing glycolide willdegrade fastest rate, polyols containing l-lactide will degrade at aslowest rate and polyol containing d-l-lactide will degrade at anintermediate rate. In one embodiment, it is expected that that forcopolymer polyols where the polycaprolactone is greater than or about 80mole % in the copolymer polyol, polyols containing glycolide willdegrade fastest rate, polyols containing l-lactide will degrade at aslowest rate and polyol containing d-l-lactide will degrade at anintermediate rate. Degradation of the soft segment of the at leastpartially degradable or fully degradable elastomeric matrix occurs owingto hydrolytic degradation and possibly also due to enzymaticdegradation. Degradation of both hard and soft segments of the fullydegradable elastomeric matrix occurs owing to hydrolytic degradation andpossibly also due to enzymatic degradation.

The degradable part of the partially degradable matrix comprising of thedegradable polyol component will degrade or hydrolyze or absorb orbioabsorb over a period of time in about 30 days. In another embodiment,degradable part of the partially degradable matrix comprising of thedegradable polyol component will degrade or hydrolyze or absorb orbioabsorb over a period of time in about 180 days. In anotherembodiment, degradable part of the partially degradable matrixcomprising of the degradable polyol component will degrade or hydrolyzeor absorb or bioabsorb over a period of time in about 1 year. In anotherembodiment, degradable part of the partially degradable matrixcomprising of the degradable polyol component will degrade or hydrolyzeor absorb or bioabsorb over a period of time in about 2 years. Inanother embodiment, degradable part of the partially degradable matrixcomprising of the degradable polyol component will degrade or hydrolyzeor absorb or bioabsorb over a period of time in greater than 2 years.The fully degradable matrix comprising of the degradable polyolcomponent and degradable isocyanate component will degrade or hydrolyzeor absorb or bioabsorb over a period of time in about 180 days. Inanother embodiment, the fully degradable matrix comprising of thedegradable polyol component and degradable isocyanate component willdegrade or hydrolyze or absorb or bioabsorb over a period of time inabout 1 year. In another embodiment, the fully degradable matrixcomprising of the degradable polyol component and degradable isocyanatecomponent will degrade or hydrolyze or absorb or bioabsorb over a periodof time in about 2 years. In another embodiment, the fully degradablematrix comprising of the degradable polyol component and degradableisocyanate component will degrade or hydrolyze or absorb or bioabsorbover a period of time in greater than 2 years.

A particular type of polyol need not be limited to those formed from asingle monomeric unit. For example, a polyether-type polyol can beformed from a mixture of ethylene oxide and propylene oxide. In anotherexample poly(caprolactone-co-l-lactide)polyol can comprise ofcaprolactone and l-lactic acid. In another examplepoly(caprolactone-co-glycolide)polyol can comprise of caprolactone andglycolic acid. In another example poly(caprolactone-co d-llactide)polyol can comprise of caprolactone and d-l lactide.Furthermore, in another embodiment, mixtures, admixtures and/or blendsof polyols and copolyols can be used in the elastomeric matrix of thepresent invention. In another embodiment, the molecular weight of thepolyol is varied. In another embodiment, the functionality of the polyolis varied. In another embodiment, if difunctional polyols cannot, ontheir own, induce soft segment cross-linking, higher functionality isintroduced into the formulation through the use of a chain extendercomponent with a hydroxyl group functionality greater than about 2. Inanother embodiment, higher functionality is introduced through the useof an isocyanate component with an isocyanate group functionalitygreater than about 2.

The process also employs at least one isocyanate component and,optionally, at least one chain extender component to provide theso-called “hard segment”. For the purposes of this application, the term“isocyanate component” includes molecules comprising, on the average,about 2 isocyanate groups per molecule as well as those moleculescomprising, on the average, greater than about 2 isocyanate groups permolecule. The isocyanate groups of the isocyanate component are reactivewith reactive hydrogen groups of the other ingredients, e.g., withhydrogen bonded to oxygen in hydroxyl groups and with hydrogen bonded tonitrogen in amine groups of the polyol component, chain extender,cross-linker and/or water.

In one embodiment, the average number of isocyanate groups per moleculein the isocyanate component is about 2. In another embodiment, theaverage number of isocyanate groups per molecule in the isocyanatecomponent is greater than about 2. In another embodiment, the averagenumber of isocyanate groups per molecule in the isocyanate component isgreater than 2. In another embodiment, the number of isocyanate groupsper molecule in the isocyanate component is greater than 2 which allowsfor cross-linking of elastomeric matrix. In one embodiment, the numberof isocyanate groups per molecule in the isocyanate component is greaterthan 2 which allows for cross-linking of isocyanate comprising hardsegment.

The soft segment part of the partially degradable and fully degradablereticulated elastomeric matrix comprises the polyol and constitutesabout 50 to about 90 mole percent. In another embodiment, the softsegment of the partially degradable and fully degradable reticulatedelastomeric matrix comprises the polyol and constitutes about 60 toabout 80 mole percent. In another embodiment, the soft segment of thepartially degradable and fully degradable reticulated elastomeric matrixcomprises the polyol and constitutes about 65 to about 75 mole percent.The hard segment comprising the isocyanate, the cross-linker and theoptional chain extender comprises the remaining mole percent.

The isocyanate index is the mole ratio of the number of isocyanategroups in a formulation available for reaction to the number of groupsin the formulation that are able to react with those isocyanate groups,e.g., the reactive groups of diol(s), polyol component(s), chainextender(s) and water, when present. In one embodiment, the isocyanateindex is from about 0.9 to about 1.1. In another embodiment, theisocyanate index is from about 0.85 to about 1. In another embodiment,the isocyanate index is from about 0.85 to about 1.01. In anotherembodiment, the isocyanate index is from about 0.9 to about 1.02. Inanother embodiment, the isocyanate index is from about 0.98 to about1.02. In another embodiment, the isocyanate index is from about 0.95 toabout 1.025. In another embodiment, the isocyanate index is from about0.9 to about 1.0. In another embodiment, the isocyanate index is fromabout 0.85 to about 1.05. In another embodiment, the isocyanate index isfrom about 0.90 to about 1.0. In another embodiment, the isocyanateindex is below 1.02. In another embodiment, the isocyanate index isbelow 1.01. In another embodiment, the isocyanate index is below 1.0. Inanother embodiment, the isocyanate index is from about 0.9 to about0.98. In another embodiment, the isocyanate index is from about 0.9 toabout 1.05.

The hard segment is derived from the isocyanate component. Exemplarydiisocyanates for at least partially degradable reticulated elastomericmatrix include aliphatic diisocyanates, isocyanates comprising aromaticgroups, the so-called “aromatic diisocyanates”, or a mixture thereof.Aliphatic diisocyanates include tetramethylene diisocyanate,cyclohexane-1,2-diisocyanate, cyclohexane-1,4-diisocyanate,hexamethylene diisocyanate, isophorone diisocyanate,methylene-bis-(p-cyclohexyl isocyanate) (“H₁₂ MDI”), cyclohexyldiisocyanate or a mixture thereof. Aromatic diisocyanates includep-phenylene diisocyanate, 4,4′-diphenylmethane diisocyanate(“4,4′-MDI”), 2,4′-diphenylmethane diisocyanate (“2,4′-MDI”),2,4-toluene diisocyanate (“2,4-TDI”), 2,6-toluenediisocyanate(“2,6-TDI”), m-tetramethylxylene diisocyanate, or a mixturethereof.

Exemplary isocyanate components for at least partially degradablereticulated elastomeric matrix comprising, on the average, greater thanabout 2 isocyanate groups per molecule, include an adduct ofhexamethylene diisocyanate and water comprising about 3 isocyanategroups, available commercially as MONDUR 1488, Mondur 1488 and MondurMRS 20 from Bayer, RUBINATE 9433 and RUBINATE 9258, each from Huntsman,H₁₂ MDI, such as DESMODUR W from Bayer and a trimer of hexamethylenediisocyanate comprising about 3 isocyanate groups, availablecommercially as MONDUR N3390 from Bayer.

In one embodiment, for at least partially degradable reticulatedelastomeric matrix the preferred isocyanate component contains a mixtureof at least about 5% by weight of 2,4′-MDI with the balance 4,4′-MDI. Inanother embodiment, the isocyanate component contains a mixture of atleast 5% by weight of 2,4′-MDI with the balance 4,4′-MDI. In anotherembodiment, the isocyanate component contains a mixture of from about 5%to about 50% by weight of 2,4′-MDI with the balance 4,4′-MDI. In anotherembodiment, the isocyanate component contains a mixture of from 5% toabout 50% by weight of 2,4′-MDI with the balance 4,4′-MDI. In anotherembodiment, the isocyanate component contains a mixture of from about 5%to about 40% by weight of 2,4′-MDI with the balance 4,4′-MDI. In anotherembodiment, the isocyanate component contains a mixture of from 5% toabout 40% by weight of 2,4′-MDI with the balance 4,4′-MDI. In anotherembodiment, the isocyanate component contains a mixture of from 5% toabout 35% by weight of 2,4′-MDI with the balance 4,4′-MDI. Without beingbound by any particular theory, it is thought that the use of higheramounts of 2,4′-MDI in a blend with 4,4′-MDI results in a softerelastomeric matrix because of the disruption of the crystallinity of thehard segment arising out of the asymmetric 2,4′-MDI structure. Also.Without being bound by any particular theory, it is thought that the useof higher amounts of 2,4′-MDI in a blend with 4,4′-MDI results in asofter elastomeric matrix because of the disruption of the stereoregularity of the hard segment arising out of the asymmetric 2,4′-MDIstructure. It is believed that the disruption of the crystallinity orthe stereo regularity of the hard segment arising out of the asymmetric2,4′-MDI structure, provides a less stiffer structure for thereticulated elastomeric matrix.

Exemplary diisocyanates for fully or completely degradable reticulatedelastomeric matrix include suitable aliphatic polyisocyanates includelysine methyl ester diisocyanate, lysine triisocyanate, amino acidlysine based diisocyanate and include the degradable diisocyanatedescribed in U.S. Pat. No. 6,221,997.

In another embodiment, exemplary diisocyanates for fully or completelydegradable reticulated elastomeric matrix include varioushydrolytically-degradable, bridged diphenyl diisocyanates described inUS patent application 2006/0188547.

Wherein each X represents a member independently selected from:

-   -   a) —CH₂COO— (glycolic acid moiety);    -   b) —CH(CH₃)COO— (lactic acid moiety);    -   c) —CH₂CH₂OCH₂COO— (dioxanone moiety);    -   d) —CH₂CH₂CH₂CH₂CH₂COO— (caprolactone moiety);    -   e) —(CH₂)_(y)COO—, where y is an integer 2, 3, 4 and 6-24        inclusive; and    -   f) —(CH₂CH₂O)_(z)CH₂COO—, where z is an integer between 2 and        24, inclusive.

Wherein each Y represents a member independently selected from:

-   -   a) —CH₂COO— (glycolic acid moiety);    -   b) —CH(CH₃)COO— (lactic acid moiety);    -   g) —COCH(CH₃)O— (lactic ester moiety);    -   h) —COCH₂OCH₂CH₂O— (dioxanone ester moiety);    -   i) —COCH₂CH₂CH₂CH₂CH₂O— (caprolactone ester moiety);    -   j) —CO(CH₂)_(m)O—, where m is an integer between 2-4 and 6-24        inclusive; and    -   k) —COCH₂O(CH₂CH₂O)_(n)—, where n is an integer between 2 and        24, inclusive.

Wherein each R′ is hydrogen, benzyl or linear or branched alkyl groupand each p is independently an integer between 1 and 4, inclusive, Z isO or NH.

Wherein R_(n) represents one or more members selected from H, alkoxy,benzyloxy, aldehyde, halogen, carboxylic acid and —NO₂, which isattached directly or through an aliphatic chain to an aromatic ring.

The aromatic compound is selected from amine and/or carboxylic acidcontaining phenols, such as amino phenols, amino salicylic acids andamino benzoic acids.

In another embodiment, exemplary diisocyanates for fully or completelydegradable reticulated elastomeric matrix include varioushydrolytically-degradable, bridged diphenyl diisocyanates having thestructures of Formulas VI-X as described in US patent application2009/0292029.

Exemplary chain extenders include diols, diamines, alkanol amines or amixture thereof. In one embodiment, the chain extender is an aliphaticdiol having from 2 to 10 carbon atoms (C₂-C₁₀-aliphatic diol). Inanother embodiment, the diol chain extender is selected from ethyleneglycol, 1,2-propane diol, 1,3-propane diol, 1,4-butane diol, 1,5-pentanediol, diethylene glycol, triethylene glycol, 1,4 cyclohexane dimethanol,1,6 hexane diol, or a mixture thereof.

In another embodiment, the chain extender is a diamine having from 2 to10 carbon atoms (C₂-C₁₀-diamine). In another embodiment, the diaminechain extender is selected from ethylene diamine, 1,3-diaminobutane,1,4-diaminobutane, 1,5 diaminopentane, 1,6-diaminohexane,1,7-diaminoheptane, 1,8-diaminooctane, isophorone diamine, or a mixturethereof.

In another embodiment, the chain extender is an alkanol amine havingfrom 2 to 10 carbon atoms. In another embodiment, the alkanol aminechain extender is selected from diethanolamine, triethanolamine,isopropanolamine, dimethylethanolamine, methyldiethanolamine,diethylethanolamine or a mixture thereof. In another embodiment, thechain extender is formed by a reaction between a naturally-occurringamino acid and a diol.

In one embodiment, a small quantity of an optional ingredient, such as amulti-functional hydroxyl compound or other cross-linker having afunctionality greater than 2, e.g., glycerol, is present to allowcross-linking. In one embodiment glycerol is a very effectivecross-linker for the hard segment and it's incorporation in thereticulated elastomeric matrix provides a secondary source ofcross-linking in addition to functionality greater than 2 for theisocyanate. In one embodiment, incorporation of the tri-functionalglycerol in the reticulated elastomeric matrix provides a morecontrolled cross-linking to the matrix. In another embodiment, theoptional multi-functional cross-linker is present in an amount justsufficient to achieve a stable foam, i.e., a foam that does not collapseto become non-foam like. Alternatively, or in addition, polyfunctionaladducts of aliphatic and cycloaliphatic isocyanates can be used toimpart cross-linking in combination with aromatic diisocyanates.Alternatively, or in addition, polyfunctional adducts of aliphatic andcycloaliphatic isocyanates can be used to impart cross-linking incombination with aliphatic diisocyanates. In one embodiment, tri ormulti-functional amines can be is present to allow cross-linking.

Exemplary blowing agents include water and the physical blowing agents,e.g., volatile organic chemicals such as hydrocarbons, ethanol andacetone, and various fluorocarbons and their more environmentallyfriendly replacements, such as hydrofluorocarbons, chlorofluorocarbonsand hydrochlorofluorocarbons. The reaction of water with an isocyanategroup yields carbon dioxide, which serves as a blowing agent.Additionally, the reaction of water with an isocyanate group leads tothe formation of urea groups. In one embodiment, the urea groups formedduring the foaming reaction of isocyanate with water. Moreover,combinations of blowing agents, such as water with a fluorocarbon, canbe used in certain embodiments. In another embodiment, water is used asthe blowing agent. Commercial fluorocarbon blowing agents are availablefrom Huntsman, E.I. duPont de Nemours and Co. (Wilmington, Del.), AlliedChemical (Minneapolis, Minn.) and Honeywell (Morristown, N.J.).

An alternative preparation embodiment pursuant to the invention involvespartial or total replacement of water as a blowing agent withwater-soluble spheres, fillers or particles which are removed, e.g., bywashing, extraction or melting, after full cross-linking of the matrix.

Optionally, the process employs at least one catalyst in certainembodiments selected from a blowing catalyst, e.g., a tertiary amine, agelling catalyst, e.g., dibutyltin dilaurate, or a mixture thereof.Moreover tertiary amine catalysts can also have gelling effects, thatis, they can act as a blowing and gelling catalyst. Exemplary aminecatalysts include Dabco 33LV and A-133 from Air Products. In anotherembodiment, a catalyst such as, e.g., the tin catalyst, is omitted andoptionally substituted with another catalyst, e.g., a tertiary amine. Inone embodiment, the tertiary amine catalyst comprises one or morenon-aromatic amines. In another embodiment, the reaction is conducted sothat the tertiary amine catalyst, if employed, is wholly reacted intothe polymer, and residues of same are avoided. In another embodiment,the gelling catalyst is omitted and, instead, higher foamingtemperatures are used. Exemplary tertiary amine catalysts include theTOTYCAT line from Toyo Soda Co. (Japan), the TEXACAT line from TexacoChemical Co. (Austin, Tex.), the KOSMOS and TEGO lines from Th.Goldschmidt Co. (Germany), the DMP line from Rohm and Haas(Philadelphia, Pa.), the KAO LIZER line from Kao Corp. (Japan), and theQUINCAT line from Enterprise Chemical Co. (Altamonte Springs, Fla.).Exemplary organotin catalysts include the FOMREZ and FOMREZ UL linesfrom Witco Corporation (Middlebury, Conn.), the COCURE and COSCAT linesfrom Cosan Chemical Co. (Carlstadt, N.J.), and the DABCO and POLYCATlines from Air Products.

In certain embodiments, the process employs at least one surfactant.Exemplary surfactants include TEGOSTAB BF 2370, B-8300, B-8305 andB-5055, all from Goldschmidt, DC 5241 from Dow Corning (Midland, Mich.),and other non-ionic organosilicones, such as the polydimethylsiloxanetypes available from Dow Corning, Air Products and General Electric(Waterford, N.Y.).

In certain embodiments, the process employs at least one cell-opener.Exemplary cell-openers include ORTEGOL 501 from Goldschmidt. In anotherembodiment, the process employs at least viscosity modifier or viscositydepressant such as Propylene carbonate.

In certain embodiments, the soft segment comprising polyols such aspolycaprolactone polyol of the at least partially degradable elastomericmatrix is between 50 and 90% of the elastomeric matrix. In anotherembodiment, the soft segment comprising polyols such as polycaprolactonepolyol of the the at least partially degradable elastomeric matrix isbetween 60 and 80% of the elastomeric matrix. The soft segementcomprising polyols such as polycaprolactone polyol can substantially ortotally degrade or bioabsorb or bio-resorb over time. The hard segmentcomprising isocyanate such as MDI of the at least partially degradableelastomeric matrix can be between 10 and 50% of the elastomeric matrix.In another embodiment, hard segment comprising isocyanate such as MDI ofthe the at least least partially degradable elastomeric matrix isbetween 20 and 40% of the elastomeric matrix. The hard segmentcomprising isocyanate such as MDI can be substantially or totallybiostable or biodurable. In another embodiment, the hard segmentcomprising isocyanate such as MDI is partially or totally degrade orbioabsorb or bio-resorb over time. In one embodiment, the mechanism fordegradation for both hard and soft segment is hydrolytic and/orenzymatic degradation.

Cross-linked polyurethanes may be prepared by approaches which includethe prepolymer process and the one-shot process. An embodiment involvinga prepolymer is as follows. First, the prepolymer is prepared by aconventional method from the polyol diol in diisocyanate, preferablyexcess diisocyanate, to produce an isocyanate terminated molecule; thepre-polymer generally has a lower molecular weight but can have anintermediate or higher molecular weight. Subsequent reaction of thepre-polymer with a diol or diamine chain extender and/ormulti-functional hydroxyl compound constitutes the second step whichproduces a block copolymer, preferably a multi-block copolymer. Theblock copolymer can be cross-linked when the number of isocyanate groupsper molecule in the isocyanate component is greater than 2 and/or when amulti-functional hydroxyl compound or other cross-linker having afunctionality greater than 2, e.g., glycerol, is present to allowcross-linking. In another embodiment, the prepolymer is prepared from atleast one isocyanate component (e.g., methylene diphenyl diisocyanate orMDI), and at least one multi-functional soft segment material with afunctionality greater than 2 (e.g., a polyether-based soft segment witha functionality of 3). Then, the prepolymer, optionally at least onecatalyst (e.g., dibutyltin dilaurate) and at least one difunctionalchain extender (e.g., 1,4-butanediol) are admixed in a mixing vessel tocure or cross-link the mixture. In another embodiment, cross-linkingtakes place in a mold. In another embodiment, cross-linking and foaming,i.e., pore formation, take place together. In another embodiment,cross-linking and foaming take place together in a mold.

Alternatively, the so-called “one-shot” approach may be used. A one-shotembodiment requires no separate prepolymer-making step. In oneembodiment, the starting materials, such as those described in theprevious paragraphs, are admixed in a mixing vessel and then foamed andcross-linked. In embodiment, the starting materials, such as thosedescribed in the previous paragraphs are separate or some of them aremixed before they are admixed in a mixing vessel and then foamed andcross-linked. In another embodiment, the ingredients are heated beforethey are admixed. In another embodiment, only selected ingredients areheated before they are admixed. In another embodiment, at least oneingredient and no more than three ingredients are heated before they areadmixed. In another embodiment, the ingredients are heated as they areadmixed or in other words, the mixing chamber or the foaming reactor isheated. In another embodiment, cross-linking takes place in a mold. Themold can be stationary or can be moving such as conveyor belts withwalls and whose speed can be controlled. In another embodiment, foamingand cross-linking take place together. In another embodiment,cross-linking and foaming take place together in a mold. In anotherembodiment, all of the ingredients except for the isocyanate componentare admixed in a mixing vessel. The isocyanate component is then added,e.g., with high-speed stirring, and cross-linking and foaming ensues. Inanother embodiment, this foaming mix is poured into a mold and allowedto rise.

In another embodiment, the polyol component is admixed with theisocyanate component and other optional additives, such as a viscositymodifier, surfactant and/or cell opener, to form a first liquid. Inanother embodiment, the polyol component is a liquid at the mixingtemperature. In another embodiment, the polyol component is a solid,therefore, the mixing temperature is raised such that the polyolcomponent is liquefied prior to mixing, e.g., by heating. Next, a secondliquid is formed by admixing a blowing agent and cross-linker with anyoptional additives, such as gelling catalyst and/or blowing catalyst.The blowing agent is preferably water and in embodiment is distilledwater. The cross-linking agent is glycerol. Then, the first liquid andthe second liquid are admixed in a mixing vessel and then foamed andcross-linked. In another embodiment, foaming and cross-linking occursimultaneously. The foaming mix is poured optionally through a nozzleinto a mold and allowed to rise. In one embodiment, the process can be“one-shot” approach. In another embodiment, the process can follow thepre-polymer approach.

In another embodiment of the one-shot approach, the isocyanate componentforms a first liquid. In one embodiment, the isocyanate component ismaintained between 5 psi and 30 psi above the ambient pressure and inanother embodiment, the isocyanate component is optionally maintainedbetween 20° C. to 30° C. The polyol component is admixed with otheroptional additives, such as a viscosity modifier, and/or cell opener, toform a second liquid. In another embodiment, the polyol component is aliquid at the mixing temperature. In another embodiment, the polyolcomponent is a liquid at the mixing temperature or in anotherembodiment, the polyol component is a liquid at room temperature. Inanother embodiment, the polyol component is a solid, therefore, themixing temperature is raised such that the polyol component is liquefiedprior to mixing, e.g., by heating. In one embodiment, the temperature ofthe polyol can be between 50° C. and 90° C. In one embodiment, thepolyol component is admixed or pre-mixed with cell opener and viscositydepressant. In another the polyol component is optionally admixed orpre-mixed with cell opener and viscosity depressant. Next, a thirdliquid is formed by admixing a blowing agent and a cross-liner andoptionally a chain extender and optional additives, such as gellingcatalyst and/or blowing catalyst and surfactants. The blowing agent ispreferably water and in embodiment is distilled water. The cross-linkingagent is glycerol. In one embodiment the blowing agent, water, andcross-linking agent, glycerol, are always admixed before the foaming andcross-linking reactions. Then, the first liquid, the second liquid andthe third liquid are admixed in a mixing vessel and then foamed andcross-linked. In another embodiment, foaming and cross-linking occursimultaneously. In another embodiment, this foaming mix is pouredoptionally through a nozzle into a mold and allowed to rise.Considerations must be taken to ensure that the foaming fluid or thereacting mix is laid down on to the mold bottom surface in a linearfashion or without effective retracing of the flow paths so that it doesnot introduce any flow disturbances or mix up of the differently agedfoaming fluid or the reacting mix coming out of the mixing vessel. Inone embodiment, the foaming fluid or the reacting mix is laid down on tothe mold bottom surface in a linear fashion or without effectiveretracing of the flow paths such that the foaming fluid or the reactingmix coming out of the mixing vessel at a later time do not introduce anyflow disturbances or mix with foaming fluid or the reacting mix thatcame out earlier.

In another embodiment of the one-shot process, the delivery system forthe polyol component is placed inside a heated compartment to maintainthe material as a liquid and accurately maintain temperature control. Inanother embodiment, the isocyanate component is maintained in acontinuously stirred vessel under greater than ambient pressure, between5 psi and 75 psi above the ambient pressure, to increase nucleationsites available during the reaction process. In another embodiment,isocyanate component is maintained in a continuously stirred vesselunder greater than ambient pressure, preferably between 15 psi and 60psi above the ambient pressure. Higher pressure helps to provide morenucleation leading to finer sized or smaller sized cells. In oneextreme, vacuum can be applied to provide larger sized or coarse sizedcells. Thus appropriate section of pressure is critical for controllingthe cell size. In another embodiment, the reactive components along withthe catalysts and surfactants are admixed and maintained in acontinuously stirred vessel. In one embodiment, the reactive componentsinclude a blowing agent and a cross-liner and a chain extender. In oneembodiment, the reactive components include a blowing agent and across-liner and a chain extender but does not include the polyolcomponent or the isocyanate component. The blowing agent is preferablywater and in embodiment is distilled water. The cross-linking agent isglycerol. In one embodiment the blowing agent, water, and cross-linkingagent, glycerol, are always admixed before the foaming and cross-linkingreactions Optionally, the cell opener or any of the chemicalconstituents could be admixed together or maintained as an independentstream.

In each of the aforementioned embodiments, the independent systems arepumped within their respective systems and controlled with the properflow rate within recirculation loops to maintain their correct and/orpre-determined proportions within the formulation and subsequentlydiverted into a mixing chamber with a high shear mixer where they arecombined to react in a continuous manner. One embodiment, the high shearmixer contains a multitude of pins and/or stationary mixing elements.The rotational speed of the mixer is maintained between 500 to 10,000rpm preferably between 5000 and 8000 rpm. Appropriate selection of thehigh speed mixing helps to maintain the consistency of the nucleationsite by controlling the distribution of the liquid-gas interface. Inanother embodiment, the mixed constituents of the formulation can beinjected at variable pressures through nozzles to further control thefluid dynamic properties of the materials within the reaction chamber.Higher injection pressures help to create finer atomization of theinjected constituents, which can have a beneficial effect on thenucleation within the resulting porous matrix. In another embodiment,the reaction mixture is poured onto a release paper coated movingconveyor with fixed walls to create a continuous steady state mold forthe foaming process. The reaction mixture or the foaming mix after beingpoured optionally through a nozzle into a mold and allowed to rise fillthe volume of the mold and are guided within the space by the walls ofthe mold. Considerations must be taken to ensure that the foaming fluidor the reacting mix is laid down on to the mold bottom surface in alinear fashion or without effective retracing of the flow paths so thatit does not introduce any flow disturbances or mix up of the differentlyaged foaming fluid or the reacting mix coming out of the mixing vessel.In one embodiment, the foaming fluid or the reacting mix is laid down onto the mold bottom surface in a linear fashion or without effectiveretracing of the flow paths such that the foaming fluid or the reactingmix coming out of the mixing vessel at a later time do not introduce anyflow disturbances or mix with foaming fluid or the reacting mix thatcame out earlier.

At the end of the foam rise, the foaming and cross-linking reaction areconsidered to be complete or substantially complete and leads to theformation of a foamed block or a foamed matrix. In one embodiment, thefoamed matrix is then optionally subjected to additional curing at anelevated temperature. The curing ensures the utilization and/or removalof any free isocyanates and amines and/or completion or substantialcompletion of other un-reacted ingredients that may not have reactedduring foam formation. The curing temperature can range from 70° C. to120° C. and in other embodiment can range from 75° C. to 110° C. Thecuring time can range from 30 minutes to 400 minutes and in otherembodiment can range from 60 minutes to 300 minutes. In one embodiment,the foamed matrix is not subjected to additional curing at an elevatedtemperature.

In another embodiment, any or all of the processing approaches of theinvention may be used to make foam with a density greater than 1.0lbs/ft³ (0.016 g/cc). In this embodiment, cross-linker(s), such asglycerol, are used; the functionality of the isocyanate component isfrom 2.0 to 2.4; the isocyanate component in case of least partiallydegradable matrix formulation consists essentially of MDI; and theamount of 4,4′-MDI is greater than about 50% by weight of the isocyanatecomponent. The molecular weight of the polyol component is from about500 to about 5,000 Daltons preferably between 1000 and 3500. The amountof blowing agent, e.g., water, is adjusted to obtain non-reticulatedfoam densities with lower amount of water leading to higher densities. Areduced amount of blowing agent may reduce the number of urea linkagesin the material. Any reduction in stiffness and/or tensile strengthand/or compressive strength caused by fewer urea linkages can becompensated for by using di-functional chain extenders, such asbutanediol, and/or increasing the density of the foam, and/or byincreasing the amount of cross-linking agent used and/or by increasingthe stereo regularity of the isocyanate component. In one embodiment,reducing the degree of cross-linking and, consequently, increasing thefoam's toughness and/or elongation to break should allow for moreefficient reticulation by improving its ability to withstand the suddenimpact of one or a plurality of reticulation steps. However if thereduction is cross-linking is too low or below a certain level, themechanical performances can become lower and the material can breakdownduring handling or during reticulation. In another embodiment, themolecular weight of the polyol can determine the flexibility and/or thetoughness and/or elongation to break. In one embodiment, highermolecular of polyol can lead to increasing the foam's toughness and/orelongation to break and allow for more efficient reticulation byimproving its ability to withstand the sudden impact of one or aplurality of reticulation steps. In another embodiment, the higherdensity foam material which results can better withstand the suddenimpact of one or a plurality of reticulation steps, e.g., tworeticulation steps, and can provide for minimal, if any, damage tostruts 16.

In one embodiment, the invention provides a process for preparing aflexible polyurethane least partially degradable or fully degradablematrix capable of being reticulated based on polycaprolactone polyolcomponent or polyol component containing copolymers of polycaprolactoneand isocyanate component starting materials. In another embodiment, aporous least partially degradable or fully degradable elastomerpolymerization process for making a resilient polyurethane matrix isprovided which process comprises admixing a polycaprolactone polyolcomponent and an aliphatic isocyanate component, for example H₁₂ MDI. Inanother embodiment, a porous least partially degradable or fullydegradable elastomer polymerization process for making a resilientpolyurethane matrix is provided which process comprises admixing apolycaprolactone polyol component and an aliphatic isocyanate component,for example, lysine methyl ester diisocyanate. In another embodiment, aporous least partially degradable or fully degradable elastomerpolymerization process for making a resilient polyurethane matrix isprovided which process comprises admixing a polycaprolactone polyolcomponent and various degradable diisocyanate described in US patentapplication 2006/0188547 A1 and US patent application 2009/0292029 andare referenced as hydrolytically-degradable bridged diphenyldiisocyanates and comprise multiple groups of polymers selected from agroup one (containing glycolic acid moiety, lactic acid moiety,dioxanone and caprolactone moiety), group two (containing glycolic estermoiety, lactic ester moiety, dioxanone ester moiety, group three(containing hydrogen, benzyl or an alkyl group, the alkyl group beingeither straight-chained or branched) and group four (selected from H,alkoxy, benzyloxy, aldehyde, halogen, carboxylic acid and —NO₂, which isattached directly to an aromatic ring or attached through an aliphaticchain)

In another embodiment, the foam is substantially free of isocyanuratelinkages. In another embodiment, the foam has no isocyanurate linkages.In another embodiment, the foam is substantially free of biuretlinkages. In another embodiment, the foam has no biuret linkages. Inanother embodiment, the foam is substantially free of allophanatelinkages. In another embodiment, the foam has no allophanate linkages.In another embodiment, the foam is substantially free of isocyanurateand biuret linkages. In another embodiment, the foam has no isocyanurateand biuret linkages. In another embodiment, the foam is substantiallyfree of isocyanurate and allophanate linkages. In another embodiment,the foam has no isocyanurate and allophanate linkages. In anotherembodiment, the foam is substantially free of allophanate and biuretlinkages. In another embodiment, the foam has no allophanate and biuretlinkages. In another embodiment, the foam is substantially free ofallophanate, biuret and isocyanurate linkages. In another embodiment,the foam has no allophanate, biuret and isocyanurate linkages. Withoutbeing bound by any particular theory, it is thought that the absence ofallophanate, biuret and/or isocyanurate linkages provides an enhanceddegree of flexibility to the elastomeric matrix because of lowercross-linking of the hard segments.

In certain embodiments, additives helpful in achieving a stable foam,for example, surfactants and catalysts, can be included. By limiting thequantities of such additives to the minimum desirable while maintainingthe functionality of each additive, the impact on the toxicity of theproduct can be controlled.

In one embodiment, elastomeric matrices of various densities, e.g., fromabout 0.008 to about 0.15 g/cc (from about 0.50 to about 9.4 lb/ft³) areproduced. In another embodiment, elastomeric matrices of variousdensities, e.g., from about 0.008 g/cc to about 0.320 g/cc (from about0.5 lb/ft³ to about 20 lb/ft³) are produced. The density is controlledby, e.g., the amount of blowing or foaming agent, the isocyanate index,the isocyanate component content in the formulation, the reactionexotherm, and/or the pressure of the foaming environment.

For the purpose of embodiments of the invention, for every 100 parts byweight (or 100 grams) of polyol component (e.g., polycaprolactonepolyol, polyol, poly (caprolactone-co-l-lactide)polyol,poly(caprolactone-co-glycolide)polyol, polyol or poly(caprolactone-co-d/l-lactide)) that can be used to make an elastomericmatrix through foaming and cross-linking, the amounts of the othercomponents present, by weight, in a formulation are as follows: fromabout 10 to about 90 parts (or grams) isocyanate component (e.g., MDIs,their mixtures, H₁₂MDI, lysine methyl ester diisocyanate, degradablediisocyanate described in US patent application 2006/0188547 A1) with anisocyanate index of from about 0.85 to about 1.05 preferably from about0.90 to about 1.02, from about 0.5 to about 6.0 parts (or grams) blowingagent (e.g., water), from about 0.1 to about 2.0 parts (or grams)blowing catalyst (e.g., tertiary amine), from about 0.1 to about 8.0parts (or grams) surfactant, and from about 0.1 to about 8.0 parts (orgrams) cell opener. The amount of isocyanate component is related to anddepends upon the magnitude of the isocyanate index for a particularformulation. Additionally, for every 100 parts by weight (or 100 grams)of polyol component that can be used to make an elastomeric matrixthrough foaming and cross-linking, the amounts of the following optionalcomponents, when present in a formulation, are as follows by weight: upto about 20 parts (or grams) chain extender, up to about 20 parts (orgrams) cross-linker, up to about 0.5 parts (or grams) gelling catalyst(e.g., a compound comprising tin), up to about 10.0 parts (or grams)physical blowing agent (e.g., hydrocarbons, ethanol, acetone,fluorocarbons), and optionally up to about 15 parts (or grams) viscositymodifier. The isocyanate is maintained between 15 and 60 psi andoptionally between 20 and 55 psi. The mixing speed is between 5000 and8000 rpm. The foaming fluid or the reacting mix is laid down on to themold bottom surface in a linear fashion or without effective retracingof the flow paths.

In other embodiments, for every 100 parts by weight (or 100 grams) ofpolyol component (e.g., polycaprolactone polyol, polyol, poly(caprolactone-co-l-lactide) polyol, poly(caprolactone-co-glycolide)polyol or poly (caprolactone-co-d/l-lactide)) that can be used to makean elastomeric matrix through foaming and cross-linking, the amounts ofthe other components present, by weight, in a formulation are asfollows: from about 10 to about 90 parts (or grams) isocyanate component(e.g., MDIs, their mixtures, H₁₂MDI, lysine methyl ester diisocyanate,degradable diisocyanate described in US patent application 2006/0188547A1 and US patent application 2009/0292029) with an isocyanate index offrom about from about 0.85 to about 1.019 in another embodiment, fromabout 0.5 to about 6.0 parts (or grams) blowing agent (e.g., water),optionally, from about 0.05 to about 3.0 parts (or grams) catalyst(e.g., tertiary amine), such as a blowing catalyst and/or gellingcatalyst, from about 0.1 to about 8.0 parts (or grams) surfactant,optionally, from about 0.1 to about 8.0 parts (or grams) cell opener,optionally, from about 0.05 to about 8.0 parts (or grams) cross-linkingagent, e.g., glycerine, and optionally, from about 0.05 to about 8.0parts (or grams) chain extender, e.g., 1,4-butanediol. The isocyanate ismaintained between 15 and 60 psi and optionally between 20 and 55 psi.The mixing speed is between 5000 and 8000 rpm. The foaming fluid or thereacting mix is laid down on to the mold bottom surface in a linearfashion or without effective retracing of the flow paths.

Matrices with appropriate properties for the purposes of embodiments ofthe invention, as determined by testing, for example, acceptablecompression set at human body temperature, airflow, tensile strength andcompressive properties, can then be reticulated.

The matrix that are made by polymerization, cross-linking and foamingform cells and pores forms a porous matrix that still needs to undergofurther processing during reticulation. The membranes or the cell wallscan be formed during the synthesis of the scaffold material or matrix bypolymerization, cross-linking and foaming that can result in theformation of cells and cell walls. In one embodiment, the reticulationprocess substantially or fully removes at least a portion of the cellwalls or membranes from the cells and pores. In another embodiment, thereticulation process substantially or fully removes the cell walls andmembranes from the cells and pores.

Not all porous foams irrespective of their composition or structure canbe reticulated without causing damage to their struts or having theability to at least partially, substantially or totally remove the cellwalls or membranes or windows. There are several factors that provideeffective and efficient reticulation to remove or substantially removethe cell walls or membranes or windows formed during the foaming processcomprising by polymerization, cross-linking and foaming. One such factoris the reduction of the degree of crosslinking and consequentlyincreasing the foam's toughness and/or elongation to break thus allowingfor more efficient and/or effective reticulation. This is because theresulting structures, with higher toughness and/or elongation to break,can have the ability, to withstand the sudden impact in a reticulationprocess with minimal, if any, damage to struts that surround the cellsand the pores. But too low cross-linking can lead to less resilience,less pronounced elastomeric behavior and lower tensile and compressionproperties. As discussed earlier, one way to lower the degree ofcrosslinking is by keeping the matrix substantially or totally free ofallophanate, biuret and isocyanurate linkages. In another embodiment, amore flexible matrix can withstand the sudden impact in a reticulationprocess with minimal, if any, damage to struts that form the cells andpores. One way to increase the flexibility of the matrix is to select anappropriate molecular weight for the polyol and without being bound byany particular theory, a higher molecular weight of polyol leads to moreflexible matrix. Also for the reticulation process to be efficient andeffective, there must be adequate passage for gaseous exchange duringevacuation of air from the foamed matrix and during the saturation ofcombustible gases before ignition. There are other important variablesthat need to be controlled such as void content, cell size, celldistribution, mechanical strength and modulus, etc. in thepre-reticulated matrix for the reticulation to be efficient in creatingthe interconnected and inter-communicating network of cells and pores.It is thus evident that there needs to be a balance between thestructure and properties of the matrix before reticulation for thereticulation process to be efficient in creating accessibleinter-connected and inter-communicating pores and cells. Thus, thedesigning the appropriate chemical composition, formulation of variousingredients, and structure of the matrix with a right balance isextremely important for creation of the matrix that can be usedeffectively for efficient reticulation. The selection and design of theappropriate chemical composition, formulation of various ingredients,and structure of the matrix to obtain effective and efficientreticulation are novel, non-obvious and non-trivial when compared tonormal foaming processes. In one embodiment, the selection and design ofthe appropriate chemical composition, formulation of variousingredients, and structure of the matrix to obtain effective andefficient reticulation are novel, non-obvious and non-trivial whencompared to normal foaming processes with similar void content, range ofpore size, and even some similarity in some of the starting ingredients.In another embodiment, to enhance biocompatibility, ingredients for thepolymerization process are selected so as to avoid or minimize thepresence in the end product elastomeric matrix of biologically adversesubstances or substances susceptible to biological attack.

Reticulation of Elastomeric Matrices

Elastomeric matrix 10 can be subjected to any of a variety ofpost-processing treatments to enhance its utility, some of which aredescribed herein and others. In one embodiment, reticulation of anelastomeric matrix 10 of the invention, if not already a part of thedescribed production process, may be used to remove at least a portionof any existing interior “windows”, i.e., the residual membranes or cellwalls 22 illustrated in FIG. 1. Reticulation tends to increase fluidpermeability.

Porous or foam materials with some ruptured cell walls are generallyknown as “open-cell” materials or foams. In contrast, porous materialsknown as “reticulated” or “at least partially reticulated” have many,i.e., at least about 40%, of the cell walls that would be present in anidentical porous material except composed exclusively of cells that areclosed, at least partially removed. Where the cell walls are leastpartially removed by reticulation, adjacent reticulated cells open into,interconnect with, and communicate with each other. Porous materialsfrom which more, i.e., at least about 65%, of the cell walls have beenremoved are known as “further reticulated”. If most, i.e., at leastabout 80%, or substantially all, i.e., at least about 90%, of the cellwalls have been removed then the porous material that remains is knownas “substantially reticulated” or “fully reticulated”, respectfully. Itwill be understood that, pursuant to this art usage, a reticulatedmaterial or foam comprises a network of at least partially openinterconnected cells.

“Reticulation” generally refers to a process for at least partiallyremoving cell walls, not merely rupturing or tearing them by a crushingprocess. Moreover, crushing undesirable and creates debris that must beremoved by further processing. In another embodiment, the reticulationprocess substantially fully removes at least a portion of the cellwalls. Reticulation may be effected, for example, by at least partiallydissolving away cell walls, known variously as “solvent reticulation” or“chemical reticulation”; or by at least partially melting, burningand/or exploding out cell walls, known variously as “combustionreticulation”, “thermal reticulation” or “percussive reticulation”.Melted material arising from melted cell walls can be deposited on thestruts. In one embodiment, such a procedure may be employed in theprocesses of the invention to reticulate elastomeric matrix 10. Inanother embodiment, all entrapped air in the pores of elastomeric matrix10 is evacuated by application of vacuum prior to reticulation. Inanother embodiment, reticulation is accomplished through a plurality ofreticulation steps. In another embodiment, two reticulation steps areused. In another embodiment, a first combustion reticulation is followedby a second combustion reticulation. In another embodiment, combustionreticulation is followed by chemical reticulation. In anotherembodiment, chemical reticulation is followed by combustionreticulation. In another embodiment, a first chemical reticulation isfollowed by a second chemical reticulation.

In one embodiment relating to orthopedic applications and the like, theelastomeric matrix 10 can be reticulated to provide an interconnectedpore structure, the pores having an average diameter or other largesttransverse dimension of at least about 10 μm. In another embodiment, theelastomeric matrix can be reticulated to provide pores with an averagediameter or other largest transverse dimension of at least about 20 μm.In another embodiment, the elastomeric matrix can be reticulated toprovide pores with an average diameter or other largest transversedimension of at least about 50 μm. In another embodiment, theelastomeric matrix can be reticulated to provide pores with an averagediameter or other largest transverse dimension of at least about 150 μm.In another embodiment, the elastomeric matrix can be reticulated toprovide pores with an average diameter or other largest transversedimension of at least about 250 μm. In another embodiment, theelastomeric matrix can be reticulated to provide pores with an averagediameter or other largest transverse dimension of greater than about 250μm. In another embodiment, the elastomeric matrix can be reticulated toprovide pores with an average diameter or other largest transversedimension of greater than 250 μm. In another embodiment, the elastomericmatrix can be reticulated to provide pores with an average diameter orother largest transverse dimension of at least about 450 μm. In anotherembodiment, the elastomeric matrix can be reticulated to provide poreswith an average diameter or other largest transverse dimension ofgreater than about 450 μm. In another embodiment, the elastomeric matrixcan be reticulated to provide pores with an average diameter or otherlargest transverse dimension of greater than 450 μm. In anotherembodiment, the elastomeric matrix can be reticulated to provide poreswith an average diameter or other largest transverse dimension of atleast about 500 μm.

[000184] In another embodiment relating to orthopedic applications andthe like, the elastomeric matrix can be reticulated to provide poreswith an average diameter or other largest transverse dimension of notgreater than about 600 μm. In another embodiment, the elastomeric matrixcan be reticulated to provide pores with an average diameter or otherlargest transverse dimension of not greater than about 450 μm. Inanother embodiment, the elastomeric matrix can be reticulated to providepores with an average diameter or other largest transverse dimension ofnot greater than about 250 μm. In another embodiment, the elastomericmatrix can be reticulated to provide pores with an average diameter orother largest transverse dimension of not greater than about 150 μm. Inanother embodiment, the elastomeric matrix can be reticulated to providepores with an average diameter or other largest transverse dimension ofnot greater than about 20 μm. [000185] In another embodiment relating toorthopedic applications and the like, the elastomeric matrix can bereticulated to provide pores with an average diameter or other largesttransverse dimension of from about 10 μm to about 50 μm. In anotherembodiment, the elastomeric matrix can be reticulated to provide poreswith an average diameter or other largest transverse dimension of fromabout 20 μm to about 150 μm. In another embodiment, the elastomericmatrix can be reticulated to provide pores with an average diameter orother largest transverse dimension of from about 150 μm to about 250 μm.In another embodiment, the elastomeric matrix can be reticulated toprovide pores with an average diameter or other largest transversedimension of from about 250 μm to about 500 μm. In another embodiment,the elastomeric matrix can be reticulated to provide pores with anaverage diameter or other largest transverse dimension of from about 450μm to about 600 μm. In another embodiment, the elastomeric matrix can bereticulated to provide pores with an average diameter or other largesttransverse dimension of from about 10 μm to about 500 μm. In anotherembodiment, the elastomeric matrix can be reticulated to provide poreswith an average diameter or other largest transverse dimension of fromabout 10 μm to about 600 μm.

Optionally, the reticulated elastomeric matrix may be purified, forexample, by solvent extraction, either before or after reticulation. Anysuch solvent extraction, such as with isopropyl alcohol, or otherpurification process is, in one embodiment, a relatively mild processwhich is conducted so as to avoid or minimize possible adverse impact onthe mechanical or physical properties of the elastomeric matrix that maybe necessary to fulfill the objectives of this invention.

One embodiment employs chemical reticulation, where the elastomericmatrix is reticulated in an acid bath comprising an inorganic acid.Another embodiment employs chemical reticulation, where the elastomericmatrix is reticulated in a caustic bath comprising an inorganic base.Another embodiment employs solvent reticulation, where a volatilesolvent that leaves no residue is used in the process. Anotherembodiment employs solvent reticulation at a temperature elevated above25° C. In another embodiment, an elastomeric matrix comprisingpolycaprolactone polyurethane is solvent reticulated with a solventselected from tetrahydrofuran (“THF”), dimethyl acetamide (“DMAC”),dimethyl sulfoxide (“DMSO”), dimethylformamide (“DMF”),N-methyl-2-pyrrolidone, also known as m-pyrol, or a mixture thereof. Inanother embodiment, an elastomeric matrix comprising polycaprolactonepolyurethane is solvent reticulated with THF. In another embodiment, anelastomeric matrix comprising polycaprolactone polyurethane is solventreticulated with N-methyl-2-pyrrolidone. In another embodiment, anelastomeric matrix comprising polycaprolactone polyurethane ischemically reticulated with a strong base. In another embodiment, the pHof the strong base is at least about 9.

In any of these chemical or solvent reticulation embodiments, thereticulated foam can optionally be washed. In any of these chemical orsolvent reticulation embodiments, the reticulated foam can optionally bedried.

In one embodiment, combustion reticulation may be employed in which acombustible atmosphere, e.g., a mixture of hydrogen and oxygen ormethane and oxygen, is ignited, e.g., by a spark. In another embodiment,combustion reticulation is conducted in a pressure chamber. In anotherembodiment, the pressure in the pressure chamber is substantiallyreduced, e.g., to below about 50-150 millitorr by evacuation for atleast about 2 minutes, before, e.g., hydrogen, oxygen or a mixturethereof, is introduced. In another embodiment, the pressure in thepressure chamber is substantially reduced in more than one cycle, e.g.,the pressure is substantially reduced, an unreactive gas such as argonor nitrogen is introduced then the pressure is again substantiallyreduced, before hydrogen, oxygen or a mixture thereof is introduced. Thetemperature at which reticulation occurs can be influenced by, e.g., thetemperature at which the chamber is maintained and/or by thehydrogen/oxygen ratio in the chamber. In another embodiment, combustionreticulation is followed by an annealing period. In any of thesecombustion reticulation embodiments, the reticulated foam can optionallybe washed. In any of these combustion reticulation embodiments, thereticulated foam can optionally be dried.

In one embodiment, the reticulated elastomeric matrix's permeability toa fluid, e.g., a liquid, is greater than the permeability to the fluidof an unreticulated matrix from which the reticulated elastomeric matrixwas made. In another embodiment, the reticulation process is conductedto provide an elastomeric matrix configuration favoring cellularingrowth and proliferation into the interior of the matrix. In anotherembodiment, the reticulation process is conducted to provide anelastomeric matrix configuration which favors cellular ingrowth andproliferation throughout the elastomeric matrix configured forimplantation, as described herein. The permeability or Darcypermeability as measured by a Permeameter (made by PMI, Ithaca, N.Y.) ofthe foamed elastomeric matrix prior to reticulation is below 10 and inmost cases below 5. Subjecting the foamed elastomeric matrix prior toreticulation to crushing (where the matrix is compressed multiple times(greater than 5 or grater than 10) at compression greater than 50% or incases above 75%) does not change the permeability or Darcy permeabilityfrom that of the foamed elastomeric matrix prior to reticulation. Thepermeability or Darcy permeability is at least above 100 in oneembodiment of the present invention. In another embodiment, permeabilityor Darcy permeability is at least above 400. In another the permeabilityor Darcy permeability is at least above 600.

The term “configure” and the like is used to denote the arranging,shaping and dimensioning of the respective structure to which the termis applied. Thus, reference to a structure as being “configured” for apurpose is intended to reference the whole spatial geometry of therelevant structure or part of a structure as being selected or designedto serve the stated purpose.

In any of these chemical or solvent reticulation embodiments, thereticulated foam can optionally be washed. In any of these chemical orsolvent reticulation embodiments, the reticulated foam can optionally bedried.

In one embodiment, combustion reticulation may be employed in which acombustible atmosphere, e.g., a mixture of hydrogen and oxygen ormethane and oxygen, is ignited, e.g., by a spark. In another embodiment,combustion reticulation is conducted in a pressure chamber. In anotherembodiment, the pressure in the pressure chamber is substantiallyreduced, e.g., to below about 50-150 millitorr by evacuation for atleast about 2 minutes, before, e.g., hydrogen, oxygen or a mixturethereof, is introduced. In another embodiment, the pressure in thepressure chamber is substantially reduced in more than one cycle, e.g.,the pressure is substantially reduced, an unreactive gas such as argonor nitrogen is introduced then the pressure is again substantiallyreduced, before hydrogen, oxygen or a mixture thereof is introduced. Thetemperature at which reticulation occurs can be influenced by, e.g., thetemperature at which the chamber is maintained and/or by thehydrogen/oxygen ratio in the chamber. In another embodiment, combustionreticulation is followed by an annealing period. In any of thesecombustion reticulation embodiments, the reticulated foam can optionallybe washed. In any of these combustion reticulation embodiments, thereticulated foam can optionally be dried.

In one embodiment, the reticulated elastomeric matrix's permeability toa fluid, e.g., a liquid, is greater than the permeability to the fluidof an unreticulated matrix from which the reticulated elastomeric matrixwas made. In another embodiment, the reticulation process is conductedto provide an elastomeric matrix configuration favoring cellularingrowth and proliferation into the interior of the matrix. In anotherembodiment, the reticulation process is conducted to provide anelastomeric matrix configuration which favors cellular ingrowth andproliferation throughout the elastomeric matrix configured forimplantation, as described herein. The permeability or Darcypermeability as measured by a Permeameter (made by PMI, Ithaca, N.Y.) ofthe foamed elastomeric matrix prior to reticulation is below 10 and inmost cases below 5. Subjecting the foamed elastomeric matrix prior toreticulation to crushing (where the matrix is compressed multiple times(greater than 5 or grater than 10) at compression greater than 50% or incases above 75%) does not change the permeability or Darcy permeabilityfrom that of the foamed elastomeric matrix prior to reticulation. Thepermeability or Darcy permeability is at least above 200 in oneembodiment of the present invention. In another embodiment, permeabilityor Darcy permeability is at least above 400. In another the permeabilityor Darcy permeability is at least above 600.

The term “configure” and the like is used to denote the arranging,shaping and dimensioning of the respective structure to which the termis applied. Thus, reference to a structure as being “configured” for apurpose is intended to reference the whole spatial geometry of therelevant structure or part of a structure as being selected or designedto serve the stated purpose.

Imparting Endopore Features

Within pores 20, elastomeric matrix 10 may, optionally, have features inaddition to the void or gas-filled volume described above. In oneembodiment, elastomeric matrix 10 may have what are referred to hereinas “endopore” features as part of its microstructure, i.e., features ofelastomeric matrix 10 that are located “within the pores”. In oneembodiment, the internal surfaces of pores 20 may be “endoporouslycoated”, i.e., coated or treated to impart to those surfaces a degree ofa desired characteristic.

Furthermore, one or more coatings may be applied endoporously bycontacting with a film-forming biocompatible polymer either in a liquidcoating solution or in a melt state under conditions suitable to allowthe formation of a biocompatible polymer film. In one embodiment, thepolymers that can be used for such coatings are film-formingbiocompatible polymers with sufficiently high molecular weight so as notto be waxy or tacky. The polymers should also adhere to the solid phase12. In another embodiment, the bonding strength is such that the polymerfilm does not crack or dislodge during handling or deployment ofreticulated elastomeric matrix 10.

Suitable biocompatible polymers include polyamides, polyolefins,nonabsorbable polyesters, and preferably bioabsorbable aliphaticpolyesters (e.g., homopolymers and copolymers of lactic acid, glycolicacid, lactide, glycolide, para-dioxanone, trimethylene carbonate,ε-caprolactone or a mixture thereof). Further, biocompatible polymersinclude film-forming bioabsorbable polymers; these include aliphaticbioabsorbable polyesters, poly(amino acids), copoly(ether-esters),polyalkylenes oxalates, polyamides, poly(iminocarbonates),polyorthoesters, polyoxaesters including polyoxaesters containing amidogroups, polyamidoesters, polyanhydrides, polyphosphazenes, biomoleculesor a mixture thereof. For the purpose of embodiments of this inventionbioabsorbable aliphatic polyesters include polymers and copolymers oflactide (which includes lactic acid d-, l- and meso lactide),ε-caprolactone, glycolide (including glycolic acid), hydroxybutyrate,hydroxyvalerate, para-dioxanone, trimethylene carbonate (and its alkylderivatives), 1,4-dioxepan-2-one, 1,5-dioxepan-2-one,6,6-dimethyl-1-1,4-dioxan-2-one or a mixture thereof. In one embodiment,the reinforcement can be made from biopolymer, such as collagen,elastin, and the like. The biopolymer can be biodegradable orbioabsorbable.

Biocompatible polymers further include film-forming biodurable polymerswith relatively low chronic tissue response, such as polyurethanes,silicones, poly(meth)acrylates, polyesters, polyalkyl oxides (e.g.,polyethylene oxide), polyvinyl alcohols, polyethylene glycols andpolyvinyl pyrrolidone, as well as hydrogels, such as those formed fromcross-linked polyvinyl pyrrolidinone and polyesters. Other polymers canalso be used as the biocompatible polymer provided that they can bedissolved, cured or polymerized. Such polymers and copolymers includepolyolefins, polyisobutylene and ethylene-α-olefin copolymers; acrylicpolymers (including methacrylates) and copolymers; vinyl halide polymersand copolymers, such as polyvinyl chloride; polyvinyl ethers, such aspolyvinyl methyl ether; polyvinylidene halides such as polyvinylidenefluoride and polyvinylidene chloride; polyacrylonitrile; polyvinylketones; polyvinyl aromatics such as polystyrene; polyvinyl esters suchas polyvinyl acetate; copolymers of vinyl monomers with each other andwith α-olefins, such as etheylene-methyl methacrylate copolymers andethylene-vinyl acetate copolymers; acrylonitrile-styrene copolymers; ABSresins; polyamides, such as nylon 66 and polycaprolactam; alkyd resins;polycarbonates; polyoxymethylenes; polyimides; polyethers; epoxy resins;polyurethanes; rayon; rayon-triacetate; cellophane; cellulose and itsderivatives such as cellulose acetate, cellulose acetate butyrate,cellulose nitrate, cellulose propionate and cellulose ethers (e.g.,carboxymethyl cellulose and hydoxyalkyl celluloses); or a mixturethereof.

A device that is made from reticulated elastomeric matrix 10 generallyis coated by simple dip or spray coating with a polymer, optionallycomprising a pharmaceutically-active agent, such as a therapeutic agentor drug. In one embodiment, the coating is a solution and the polymercontent in the coating solution is from about 1% to about 40% by weight.In another embodiment, the polymer content in the coating solution isfrom about 1% to about 20% by weight. In another embodiment, the polymercontent in the coating solution is from about 1% to about 10% by weight.

The solvent or solvent blend for the coating solution is chosen withconsideration given to, inter alia, the proper balancing of viscosity,deposition level of the polymer, wetting rate and evaporation rate ofthe solvent to properly coat solid phase 12. In one embodiment, thesolvent is chosen such that the polymer is soluble in the solvent. Inanother embodiment, the solvent is substantially completely removed fromthe coating. In another embodiment, the solvent is non-toxic,non-carcinogenic and environmentally benign. Mixed solvent systems canbe advantageous for controlling the viscosity and evaporation rates. Inall cases, the solvent should not react with the coating polymer.Solvents include by are not limited to: acetone, N-methylpyrrolidone(“NMP”), DMSO, toluene, methylene chloride, chloroform,1,1,2-trichloroethane (“TCE”), various freons, dioxane, ethyl acetate,THF, DMF and DMAC.

In another embodiment, the film-forming coating polymer is athermoplastic polymer that is melted, enters the pores 20 of theelastomeric matrix 10 and, upon cooling or solidifying, forms a coatingon at least a portion of the solid material 12 of the elastomeric matrix10. In another embodiment, the processing temperature of thethermoplastic coating polymer in its melted form is above about 60° C.In another embodiment, the processing temperature of the thermoplasticcoating polymer in its melted form is above about 90° C. In anotherembodiment, the processing temperature of the thermoplastic coatingpolymer in its melted form is above about 120° C. In another embodiment,the processing temperature of the thermoplastic coating polymer in itsmelted form is above about 140° C.

In a further embodiment of the invention, described in more detailbelow, some or all of the pores 20 of elastomeric matrix 10 are coatedor filled with a cellular ingrowth promoter. In another embodiment, thepromoter can be foamed. In another embodiment, the promoter can bepresent as a film. The promoter can be a biodegradable or absorbablematerial to promote cellular invasion of elastomeric matrix 10 in vivo.Promoters include naturally occurring materials that can beenzymatically degraded in the human body or are hydrolytically unstablein the human body, such as fibrin, fibrinogen, collagen, elastin,hyaluronic acid and absorbable biocompatible polysaccharides, such aschitosan, starch, fatty acids (and esters thereof), glucoso-glycans andhyaluronic acid. In some embodiments, the pore surface of elastomericmatrix 10 is coated or impregnated, as described in the previous sectionbut substituting the promoter for the biocompatible polymer or addingthe promoter to the biocompatible polymer, to encourage cellularingrowth and proliferation.

In one embodiment, the coating or impregnating process is conducted soas to ensure that the product “composite elastomeric implantabledevice”, i.e., a reticulated elastomeric matrix and a coating, as usedherein, retains sufficient resiliency after compression such that it canbe delivery-device delivered, e.g., catheter, syringe or endoscopedelivered. Some embodiments of such a composite elastomeric implantabledevice will now be described with reference to collagen, by way ofnon-limiting example, with the understanding that other materials may beemployed in place of collagen, as described above.

One embodiment of the invention is a process for preparing a compositeelastomeric implantable device comprising:

a) infiltrating an aqueous collagen slurry into the pores of areticulated, porous elastomer, such as elastomeric matrix 10, which isoptionally a biodurable elastomer product or optionally at leastpartially degradable elastomeric product; and

b) removing the water, optionally by lyophilizing, to provide a collagencoating, where the collagen coating optionally comprises aninterconnected network of pores, on at least a portion of a pore surfaceof the reticulated, porous elastomer.

c) Optionally, the lyophilized collagen can be cross-linked to controlthe rate of in vivo enzymatic degradation of the collagen coating and/orto control the ability of the collagen coating to bond to elastomericmatrix 10.

Collagen may be infiltrated by forcing, e.g., with pressure, an aqueouscollagen slurry, suspension or solution into the pores of an elastomericmatrix. The collagen may be Type I, II or III or a mixture thereof. Inone embodiment, the collagen type comprises at least 90% collagen I. Theconcentration of collagen is from about 0.3% to about 2.0% by weight andthe pH of the slurry, suspension or solution is adjusted to be fromabout 2.6 to about 5.0 at the time of lyophilization. Alternatively,collagen may be infiltrated by dipping an elastomeric matrix into acollagen slurry.

Coated Implantable Devices

One or more coatings may be applied endoporously by contacting with afilm-forming biocompatible polymer either in a liquid coating solutionor in a melt state under conditions suitable to allow the formation of abiocompatible polymer film. In one embodiment, the polymers that can beused for such coatings are film-forming biocompatible polymers withsufficiently high molecular weight so as not to be waxy or tacky. Thepolymers should also preferably adhere to the solid phase or the struts.Suitable biocompatible polymers include, but are not limited to,non-degradable polymers such as polyamides, polyolefins, nonabsorbablepolyesters and preferably bioabsorbable aliphatic polyesters such ashomopolymers and copolymers of lactic acid, glycolic acid, lactide,glycolide, para-dioxanone, trimethylene carbonate, ε-caprolactone or amixture thereof. In one embodiment, the coatings can be made frombiopolymer, such as collagen, elastin, and the like. The biopolymer canbe biodegradable or bioabsorbable. Biocompatible polymers furtherinclude film-forming at least partially degradable polymers withrelatively low chronic tissue response, such as polyurethanes,silicones, poly(meth)acrylates, polyesters, polyalkyl oxides (e.g.,polyethylene oxide), polyvinyl alcohols, polyethylene glycols andpolyvinyl pyrrolidone, as well as hydrogels, such as those formed fromcross-linked polyvinyl pyrrolidinone and polyesters.

The implants, with reticulated structure with sufficient and requiredliquid permeability, can permit blood or another appropriate bodilyfluid to access interior surfaces of the implants, which surfaces areoptionally drug-bearing. This can happen due to the presence ofinter-connected, reticulated open pores that form fluid passageways orfluid permeability providing fluid access all through and to theinterior of the matrix for elution of pharmaceutically-active agents,e.g., a drug, or other biologically useful materials.

In a further embodiment of the invention, the pores of at leastpartially degradable reticulated elastomeric matrix that are used tofabricate the implants of this invention are coated or filled with acellular ingrowth promoter. In another embodiment, the promoter can befoamed. In another embodiment, the promoter can be present as a film.The promoter can be a biodegradable material to promote cellularinvasion of pores at least partially degradable reticulated elastomericmatrix that are used to fabricate the implants of this invention invivo. Promoters include naturally occurring materials that can beenzymatically degraded in the human body or are hydrolytically unstablein the human body, such as fibrin, fibrinogen, collagen, elastin,hyaluronic acid and absorbable biocompatible polysaccharides, such aschitosan, starch, fatty acids (and esters thereof), glucoso-glycans andhyaluronic acid. In some embodiments, the pore surface of the at leastpartially degradable reticulated elastomeric matrix that are used tofabricate the implants of embodiments of this invention is coated orimpregnated, as described in the previous section but substituting thepromoter for the biocompatible polymer or adding the promoter to thebiocompatible polymer, to encourage cellular ingrowth and proliferation.

Elastin, fibrin, collagen or other suitable clot-inducing material canalso be coated onto an implant to provide an additional route of clotformation and these are internal coatings provided within and preferablythroughout the pores of reticulated elastomeric matrix used. Thefunctional agents can be coated, during the fabrication of theelastomeric matrix or during manufacturing of specific devices orimplants and include synthetic and naturally derived drugs orpharmacological agents and/or other agents to promote fibroblast growthand other growth factors

If desired, the outer surfaces of the elastomeric matrix or device canbe coated with functional agents, such as those described herein,optionally employing an adjuvant that secures the functional agents tothe surfaces and to reticulated elastomeric matrix pores adjacent theouter surfaces, where the agents will become quickly available. Thefunctional agents can be coated, during the fabrication of theelastomeric matrix or during manufacturing of specific devices orimplants. Such external coatings, which may be distinguished frominternal coatings provided within and preferably throughout the pores ofreticulated elastomeric matrix used, may comprise fibrin, elastin,collagen, synthetic and naturally derived drugs or pharmacologicalagents and/or other agents to promote fibroblast growth and other growthfactors.

In one embodiment, the surfaces (internal and external) of the at leastpartially degradable reticulated elastomeric matrix are coated ortreated to render them passive or relatively non-adhesive to certainplasma and extracellular matrix proteins with the goal to mask theforeign body response to the material in vivo.

In another embodiment, the surfaces (internal and external) of the atleast partially degradable reticulated elastomeric matrix are coated ortreated to promote adhesion, adsorption, and/or absorption of desirableextracellular matrix proteins, with the end goal to promote cellularmigration, proliferation, attachment, and synthetic activity.

With regard to bio-passivating strategies for embodiments of theinvention, surface modifications that can be considered to passivate theelastomeric matrix in terms of its biologic response include, forexample, albumin (i.e., plasma protein which functions as ananti-adhesion layer, heparin which functions as an anti-coagulant,prostaglandin which functions as an inhibitor of macrophage activitythus limiting foreign body response, corticosteroid which functions asan inhibitor of macrophage activity thus limiting foreign body responseand inflammation, plasma treatment and deposition, and self assemblingpeptides).

With regard to bioactivation strategies for embodiments of theinvention, coatings and techniques that can be used to functionalize thereticulated elastomeric matrix to promote cell adhesion, proliferation,and synthetic activity include, for example, fibronectin, cell adhesionmolecules (CAMS) that contain peptides, fibronectin, laminin, heparin,fibrin glue, and fibroblast growth factors, REDV(Arginine-glutamic-acid-aspartic-acid-valine), RGD(arginine-glycine-asparrtic acid), growth factors (TGF-b family, PDGF,VEGF), platelet rich plasma (PRP), platelet Rich Fibrin Matrix (PRFM),antimicrobial agents, and pro-nectin.

Various methods that have been used for coating and surfacemodifications include, for example:

a) Surface graft polymerization—using plasma/corona discharge, gamma aswell as UV radiation techniques. This will allow coarse thickness andmolecular weight control, and may leave behind unreacted monomers;

b) Condensation reactions—biomolecules can be bound to functional groupson the surface of the reticulated elastomeric matrix material (COOH,NH₂, and OH);

c) Adsorption from solutions—many methods here, typicallypolyelectrolyte multilayer and self assembling peptide techniques; and

d) Surface segregation techniques.

In some applications, a device made from elastomeric matrix 10 can haveat least a portion of the outermost or macro surface coated or fused inorder to present a smaller macro surface area, because the internalsurface area of pores below the surface is no longer accessible. Inanother embodiment a device made from elastomeric matrix 10 or compositemesh comprising reticulated elastomeric matrix 10 or the reinforcedelastomeric matrix can have at least a portion of the outermost or macrosurface coated with a film of biocompatible polymer. In anotherembodiment a device made from elastomeric matrix 10 or composite meshcomprising reticulated elastomeric matrix 10 the reinforced elastomericmatrix can have a significant portion of the outermost or macro surfacecoated with a film of biocompatible polymer. In another embodiment adevice made from elastomeric matrix 10 or composite mesh comprisingreticulated elastomeric matrix 10 the reinforced elastomeric matrix canhave all of the outermost or macro surface coated with a film ofbiocompatible polymer. Without being bound by any particular theory, itis thought that this decreased surface area provides more predictableand easier delivery and transport through long tortuous channels insidedelivery-devices. More importantly, the coating or the film can act asor impart anti-adhesion functionality in repair of some soft tissuedefects such as in a number of hernia applications. In one embodiment,the coating or with a film of biocompatible polymer is the preferredembodiment because of the smoother surface of the coating or with a filmof biocompatible polymer in comparison to the fused surface. The coatingor the film is important to impart anti-adhesion functionality, and isespecially important in anatomic sites such as abdominal wall whereinadhesions are likely to form between internal organ structures and theexposed mesh surface. In one embodiment, the surface coating or the filmof biocompatible polymer preferably needs to be flexible that itprovides ease of delivery through trocar and endoscopes and conform tothe soft tissue healing site.

Surface coating or fusion film of biocompatible polymer alters the“porosity of the surface”, i.e., at least partially reduces thepercentage of pores open to the surface, or, in the limit, completelycloses-off the pores of a coated or fused surface, i.e., that thesurface is nonporous because it has substantially no pores remaining onthe coated or fused surface. In one embodiment, surface coating orfusion or film of biocompatible polymer completely closes-off the poresof a coated or fused surface and makes it substantially or preferablytotally impermeable to liquid or body fluid. However, surface coating orfusion or film of biocompatible polymer. However, surface coating orfusion film of biocompatible polymer still allows the internalinterconnected porous structure of elastomeric matrix 10 to remain openinternally and on other non-coated or non-fused surfaces; e.g., theportion of a coated or fused pore not at the surface remainsinterconnected to other pores, and those remaining open surfaces can beused to foster cellular ingrowth and proliferation. In one embodiment, acoated and uncoated surface are orthogonal to each other. In anotherembodiment, a coated and uncoated surface are at an oblique angle toeach other. In another embodiment, a coated and uncoated surface areadjacent. In another embodiment, a coated and uncoated surface arenonadjacent. In another embodiment, a coated and uncoated surface are incontact with each other. In another embodiment, a coated and uncoatedsurface are not in contact with each other.

In embodiment, there is one or two or three dimensional reinforcementsbetween the surface coating or film of biocompatible polymer and theinternal interconnected and inter-communicating reticulated structure ofelastomeric matrix 10 containing the uncoated surface. In anotherembodiment, there is one or two dimensional reinforcements between thesurface coating or film of biocompatible polymer and the internalinterconnected and inter-communicating reticulated structure ofelastomeric matrix 10 containing the uncoated surface. In anotherembodiment, there reinforcement between the surface coating or film ofbiocompatible polymer and the internal interconnected andinter-communicating reticulated structure of elastomeric matrix 10containing the uncoated surface and the reinforcement is atwo-dimensional reinforcement, and the two-dimensional reinforcement mayfurther comprise a grid of a plurality of one-dimensional reinforcementelements, wherein the one-dimensional reinforcement elements cross eachother's paths. In further embodiments, the two-dimensional reinforcementmay be a two-dimensional mesh made up of intersecting one-dimensionalreinforcement elements. In one embodiment, the composite mesh comprisingreticulated elastomeric matrix 10 is a multi-layered structure in whichthere is two dimensional reinforcements between the surface coating orfilm of biocompatible polymer and the internal interconnected andinter-communicating reticulated structure of elastomeric matrix 10containing the uncoated surface. In another embodiment, the compositemesh comprising reticulated elastomeric matrix 10 is a multi-layeredstructure in which there is two dimensional reinforcements comprising agrid of a plurality of one-dimensional reinforcement elements betweenthe surface coating or film of biocompatible polymer and the internalinterconnected and inter-communicating reticulated structure ofelastomeric matrix 10 containing the uncoated surface.

In other applications, one or more planes of the macro surface of animplantable device made from at least partially degradable reticulatedelastomeric matrix 10 may be coated, fused or melted to improve itsattachment efficiency to attaching means, e.g., anchors or sutures, sothat the attaching means does not tear-through or pull-out from theimplantable device. Without being bound by any particular theory,creation of additional contact anchoring macro surface(s) on theimplantable device, as described above, is thought to inhibittear-through or pull-out by providing fewer voids and greaterresistance.

The fusion and/or selective melting of the macro surface layer ofelastomeric matrix 10 can be brought about in several different ways. Inone embodiment, a knife or a blade can be used to cut a block ofelastomeric matrix 10 into sizes and shapes for making final implantabledevices can be heated to an elevated temperature. In another embodiment,a device of desired shape and size is cut from a larger block ofelastomeric matrix 10 by using a laser cutting device and, in theprocess, the surfaces that come into contact with the laser beam arefused. In another embodiment, a cold laser cutting device is used to cuta device of desired shape and size. In yet another embodiment, a heatedmold can be used to impart the desired size and shape to the device bythe process of heat compression. A slightly oversized elastomeric matrix10, cut from a larger block, can be placed into a heated mold. The moldis closed over the cut piece to reduce its overall dimensions to thedesired size and shape and fuse those surfaces in contact with theheated mold. In each of the aforementioned embodiments, the processingtemperature for shaping and sizing is greater than about 15° C. in oneembodiment. In another embodiment, the processing temperature forshaping and sizing is in excess of about 100° C. In another embodiment,the processing temperature for shaping and sizing is in excess of about130° C. In another embodiment, the layer(s) and/or portions of the macrosurface not being fused are protected from exposure by covering themduring the fusing of the macro surface.

The coating coating on the macro surface or the film of biocompatiblepolymer on the macro surface can be made from a biocompatible polymer,which can include be both biodegradable or absorbable andnon-biodegradable or non-absorbable polymers or non-absorbable polymersor permanent polymers. Suitable absorbable, biodegradable,non-biodegradable, non-absorbable polymers or permanent polymers includethose biocompatible polymers disclosed in the section titled “ImpartingEndopore Features”. Exemplary biodegradable polymers that can be used ascoatings include but not limited to copolymers of caprolactone, lacticacid, glycolic acid, acid d-, l- and meso lactide and para-dioxanone,etc. or mixtures thereof. In another embodiment, biodegradable orbioabsorbable coatings made from copolymers of caprolactone with lacticacid, glycolic acid, acid d-, l- and meso lactide and para-dioxanonepara-dioxanone are considered favorable for coating applications forproviding anti-adhesion properties with copolymers of caprolactone withlactic acid in the the ratio of 40/60, 30/70 or 20/80 polycaprolactoneto polylactic acid being preferred for anti-adhesion properties.Further, the thermoplastic biodegradable or bioabsorbable polymer usedfor coating may comprise an ε-caprolactone copolymer, and optionally anε-caprolactone-lactic acid copolymer or an ε-caprolactone-lactidecopolymer. In another embodiment, biodurable or permanent biocompatiblepolymers further include polymers with relatively low chronic tissueresponse, such polyurethane such as polycarbonate polyurethanes,polysiloxane polyurethanes, poly(siloxane-co-ether) polyurethanes,polycarbonate polysiloxane polyurethanes, polycarbonate urea-urethanes,polycarbonate polysiloxane urea-urethanes and the like and theirmixtures. In another embodiment, biodurable or permanent biocompatiblepolymers include silicone. Biologically derived biomaterials areutilized as anti-adhesion coatings in other embodiments of theinvention. Examples of suitable biologically derived biomaterialsinclude reprocessed collagen, Hyaluronic acid (HA) or functionalizedproteoglycans, and any of these combined with PEG. It is to beunderstood that that listing of materials is illustrative but notlimiting. In one embodiment, surface pores are closed by applying anabsorbable polymer melt coating onto a shaped elastomeric matrix.Together, the elastomeric matrix and the coating form the device. Inanother embodiment, surface pores are closed by applying an absorbablepolymer solution coating onto a shaped elastomeric matrix to form adevice. In another embodiment, the coating and the elastomeric matrix,taken together, can occupy a larger volume than the uncoated elastomericmatrix alone.

The coating or the film coating on elastomeric matrix 10 can be appliedto the elastomeric matrix or to the reinforcements by use of an adhesiveor bonding material that can be applied in various fashion such as by,e.g., dipping or spraying a coating solution comprising a polymer or apolymer and in embodiment that solution can be admixed with apharmaceutically-active agent. In one embodiment, the polymer content inthe coating solution is from about 1% to about 40% by weight. In anotherembodiment, the polymer content in the coating solution is from about 1%to about 20% by weight. In another embodiment, the polymer content inthe coating solution is from about 1% to about 10% by weight. In anotherembodiment, the polymer content in the coating solution is from about 1%to about 10% by weight. In another embodiment, the coating may beapplied as a solution in a solvent for the polymer, for example, with apolymer content in the coating solution of from about 1% to about 40% byweight. According to other embodiments, the coating solution may beapplied by dip coating or spray coating the solution onto thereticulated elastomeric matrix, the solvent can be substantially orcompletely removed from the coating, and/or the solvent may be non-toxicand non-carcinogenic. In another embodiment, the layer(s) and/orportions of the macro surface not being solution-coated are protectedfrom exposure by covering them during the solution-coating of the macrosurface. The solvent or solvent blend for the coating solution ischosen, e.g., based on the considerations discussed in the previoussection (i.e., in the “Imparting Endopore Features” section). In oneembodiment, the coating or bonding material can be cured between 50° C.and 150° C. and in another embodiment between 60° C. and 120° C. In oneembodiment, the adhesive or bonding material can be cured between 10minutes and 3 hours and in another embodiment between 15 minutes and 2hours.

In one embodiment, the coating on elastomeric matrix 10 may be appliedby melting a film-forming coating polymer and applying the meltedpolymer onto the elastomeric matrix 10. In another embodiment, thefilm-forming coating polymer is a thermoplastic polymer that is melted,enters the pores 20 of the elastomeric matrix 10 or composite meshcomprising reticulated elastomeric matrix 10 and, upon cooling orsolidifying, forms a coating on at least a portion of the solid material12 of the elastomeric matrix 10. In other embodiments, a thermoplasticpolymer is melted and applied to coat the reticulated elastomericmatrix. In another embodiment, the coating on elastomeric matrix 10 maybe applied by melting the film-forming coating polymer and applying themelted polymer through a die, in a process such as extrusion orcoextrusion, as a thin layer of melted polymer onto a mandrel formed byelastomeric matrix 10. In either of these embodiments, the meltedpolymer coats the macro surface and bridges or plugs pores of thatsurface but does not penetrate into the interior to any significantdepth. Without being bound by any particular theory, this is thought tobe due to the high viscosity of the melted polymer. Thus, thereticulated nature of portions of the elastomeric matrix removed fromthe macro surface, and portions of the elastomeric matrix's macrosurface not in contact with the melted polymer, is maintained. Uponcooling and solidifying, the melted polymer forms a layer of solidcoating on the elastomeric matrix 10. In one embodiment, the processingtemperature of the melted thermoplastic coating polymer is at leastabout 60° C. In another embodiment, the processing temperature of themelted thermoplastic coating polymer is at least above about 90° C. Inanother embodiment, the processing temperature of the meltedthermoplastic coating polymer is at least above about 120° C. In anotherembodiment, the processing temperature of the melted thermoplasticcoating polymer is at least above about 140° C. The melt can be appliedby extruding or coextruding or injection molding or compression moldingor compressive molding the melt onto the reticulated elastomeric matrix.In another embodiment, the layer(s) and/or portions of the macro surfacenot being melt-coated are protected from exposure by covering themduring the melt-coating of the macro surface.

Another embodiment of the invention employs a collagen-coated compositeelastomeric implantable device, as described above, configured as asleeve extending around the implantable device. The collagen matrixsleeve can be implanted at a tissue repair and regeneration site, eitheradjacent to and in contact with that site. So located, the collagenmatrix sleeve can be useful to help retain the elastomeric matrix 10,facilitate the formation of a tissue seal and help prevent leakage. Thepresence of the collagen in elastomeric matrix 10 can be used to enhancecellular ingrowth and proliferation and improve mechanical stability, inone embodiment, by enhancing the attachment of fibroblasts to thecollagen. The presence of collagen can be used to stimulate earlierand/or more complete infiltration of the interconnected pores ofelastomeric matrix 10.

In one embodiments, the film of biocompatible polymer that is to be usedas coating is first formed by extrusion, injection molding compressionmolding or solvent casting. The film of biocompatible polymer is thenbonded to the implantable device using an adhesive. The adhesive can beapplied between the reinforcement and elastomeric matrix and cured. Inanother embodiment, the adhesive can be applied either to reinforcementor the elastomeric matrix or both before being cured. The adhesive canbe applied by dip or spray coating, painted with a brush, by use ofcustomized coating fixtures that can lay down or deliver a thin layer ofadhesive using blades with adjustable heights followed by transfer ofthe thin layer of adhesive on to the reinforcement or the elastomericmatrix or both. In one embodiment, the the film of biocompatible polymeris bonded by an adhesive applied by dip coating. Exemplary adhesivesinclude but not limited to Nusil™, Chronoflex™, Elast-Eon™ or abiodegradable polymer.

In another embodiment of the composite mesh comprising reticulatedelastomeric matrix 10, the film of biocompatible polymer is first meltbonded to the one or two dimensional reinforcements which in turn isthen bonded to reticulated elastomeric matrix the using an adhesive. Inanother embodiment of the composite mesh comprising reticulatedelastomeric matrix 10, the film of biocompatible polymer is first meltbonded to one side of the one or two dimensional reinforcements whoseother side in turn is then bonded to reticulated elastomeric matrix theusing an adhesive. In another embodiment of the composite meshcomprising reticulated elastomeric matrix 10, the film of biocompatiblepolymer is first melt bonded to the one or two dimensionalreinforcements which in turn is then bonded to reticulated elastomericmatrix containing the,uncoated surface the using an adhesive. In anotherembodiment of the composite mesh comprising reticulated elastomericmatrix 10, the film of biocompatible polymer is first melt bonded to theone or two dimensional reinforcements which in turn is then bonded toreticulated elastomeric matrix surface the using an adhesive. Exemplaryadhesives include but not limited to Nusil™, Chronoflex™, Elast-Eon™ ora biodegradable polymer.

In another embodiment of the composite mesh comprising reticulatedelastomeric matrix 10, the film of biocompatible polymer is first meltbonded to the one or two dimensional reinforcements which in turn isthen again melt bonded to reticulated elastomeric matrix. In anotherembodiment of the composite mesh comprising reticulated elastomericmatrix 10, the film of biocompatible polymer is first melt bonded to oneside ‘of the one or two dimensional reinforcements whose other side inturn is then again melt bonded to reticulated elastomeric matrix. Inanother embodiment of the composite mesh comprising reticulatedelastomeric matrix 10, the film of biocompatible polymer is first meltbonded to the one or two dimensional reinforcements which in turn isthen again melt bonded to reticulated elastomeric matrix containing theuncoated surface. In another embodiment of the composite mesh comprisingreticulated elastomeric matrix 10, the film of biocompatible polymer isfirst melt bonded to the one or two dimensional reinforcements which inturn is then again melt bonded to reticulated elastomeric matrixsurface. The melt bonding can take place by either melting or partiallymelting the film of biocompatible polymer. In another embodiment, themelt bonding can take place by either melting or partially melting the asecond film forming biocompatible coating polymer that can can includebe both biodegradable or absorbable and non-biodegradable ornon-absorbable polymers or permanent polymers. In one embodiment, themelt bonding processing temperature is at least about 60° C. In anotherembodiment, the melt bonding processing temperature is at least about90° C. In another embodiment, the melt bonding processing temperature isat least about 120° C. In another embodiment, the melt bondingprocessing temperature is at least about 140° C.

Embodiments of the invention composite mesh comprising reticulatedelastomeric and a coating include possible alternative designs andconfigurations. In embodiment, there is one or two or three dimensionalreinforcements between the surface coating or film of biocompatiblepolymer and one layer of elastomeric matrix with internal structure thatis reticulated. In embodiment, there is one or two dimensionalreinforcements between the surface coating or film of biocompatible andone layer of elastomeric matrix with internal structure that isreticulated. In both of these cases, only one layer of reticulatedstructure of elastomeric matrix comprising interconnected andinter-communicating is being reinforced and using reinforcing elementsthat can preferably be one or two dimensional. In one embodiment, thereinforcement is a two-dimensional reinforcement, and thetwo-dimensional reinforcement may further comprise a grid of a pluralityof one-dimensional reinforcement elements, wherein the one-dimensionalreinforcement elements cross each other's paths. In another embodiment,the surface coating or film of biocompatible polymer is placed,attached, adhesive bonded, melt bonded to the reticulated elastomericmatrix that is being reinforced. In another embodiment, the surfacecoating or film of biocompatible polymer is placed, attached, adhesivebonded, melt bonded to the one or two or three dimensionalreinforcements.

In one embodiment, the surface coating or film of biocompatible polymeris applied or incorporated on to a composite where the reinforcement isincorporated between two layers of the elastomeric matrix. In anotherembodiment, the surface coating or film of biocompatible polymer isapplied or incorporated on to a composite where the reinforcement isincorporated between two layers of the elastomeric matrix such as asandwich design. The surface coating or film of biocompatible polymer isplaced, attached, adhesive bonded, melt bonded to one of the two sidesthe reticulated elastomeric matrix that is being reinforced with one ortwo or three dimensional reinforcements. In another embodiment, thesurface coating or film of biocompatible polymer is placed, attached,adhesive bonded, melt bonded to both sides the reticulated elastomericmatrix that is being reinforced with one or two or three dimensionalreinforcements.

In one embodiment, the surface coating or film of biocompatible polymeris applied or incorporated on to a composite containing multiple layersof reinforcement and elastomeric matrix can be stacked in an alternatingfashion.

Pharmaceutically-Active Agent Delivery

In another embodiment, the film-forming polymer used to coat at leastpartially degradable reticulated elastomeric matrix 10 can provide avehicle for the delivery of and/or the controlled release of apharmaceutically-active agent, for example, a drug, such as is describedin the applications to which priority is claimed in U.S. PatentApplication Publication No. 2007/019108, the disclosures of which areincorporated herein by this reference. In another embodiment, thepharmaceutically-active agent is admixed with, covalently bonded to,adsorbed onto and/or absorbed into the coating of elastomeric matrix 10to provide a pharmaceutical composition. In another embodiment, thecomponents, polymers and/or blends that are used to form the foamcomprise a pharmaceutically-active agent. To form these foams, thepreviously described components, polymers and/or blends are admixed withthe pharmaceutically-active agent prior to forming the foam or thepharmaceutically-active agent is loaded into the foam after it isformed.

In one embodiment, the coating polymer and pharmaceutically-active agentcan have a common solvent. This can provide a coating that is asolution. In another embodiment, the pharmaceutically-active agent canbe present as a solid dispersion in a solution of the coating polymer ina solvent.

An at least partially degradable reticulated elastomeric matrix 10comprising a pharmaceutically-active agent may be formulated by mixingone or more pharmaceutically-active agents with the polymer used to makethe foam, with the solvent or with the polymer-solvent mixture andfoamed. Alternatively, a pharmaceutically-active agent can be coatedonto the foam, in one embodiment, using a pharmaceutically-acceptablecarrier. If melt-coating is employed, then, in another embodiment, thepharmaceutically-active agent withstands melt processing temperatureswithout substantial diminution of its efficacy.

Formulations comprising a pharmaceutically-active agent can be preparedfrom one or more pharmaceutically-active agents by admixing, covalentlybonding, adsorbing onto and/or absorbing into the same with the coatingof the at least partially degradable reticulated elastomeric matrix 10or by incorporating the pharmaceutically-active agent into additionalhydrophobic or hydrophilic coatings. The pharmaceutically-active agentmay be present as a liquid, a finely divided solid or anotherappropriate physical form. Typically, but optionally, the matrix caninclude one or more conventional additives, such as diluents, carriers,excipients, stabilizers and the like.

In another embodiment, a top coating can be applied to delay release ofthe pharmaceutically-active agent. In another embodiment, a top coatingcan be used as the matrix for the delivery of a secondpharmaceutically-active agent. A layered coating, comprising respectivelayers of fast- and slow-hydrolyzing polymer, can be used to stagerelease of the pharmaceutically-active agent or to control release ofdifferent pharmaceutically-active agents placed in the different layers.Polymer blends may also be used to control the release rate of differentpharmaceutically-active agents or to provide a desirable balance ofcoating characteristics (e.g., elasticity, toughness) and drug deliverycharacteristics (e.g., release profile). Polymers with differing solventsolubilities can be used to build-up different polymer layers that maybe used to deliver different pharmaceutically-active agents or tocontrol the release profile of a pharmaceutically-active agents.

The amount of pharmaceutically-active agent present depends upon theparticular pharmaceutically-active agent employed and medical conditionbeing treated. In one embodiment, the pharmaceutically-active agent ispresent in an effective amount. In another embodiment, the amount ofpharmaceutically-active agent represents from about 0.01% to about 60%of the coating by weight. In another embodiment, the amount ofpharmaceutically-active agent represents from about 0.01% to about 40%of the coating by weight. In another embodiment, the amount ofpharmaceutically-active agent represents from about 0.1% to about 20% ofthe coating by weight.

Many different pharmaceutically-active agents can be used in conjunctionwith the at least partially degradable reticulated elastomeric matrix.In general, pharmaceutically-active agents that may be administered viapharmaceutical compositions of this invention include, withoutlimitation, any therapeutic or pharmaceutically-active agent (includingbut not limited to nucleic acids, proteins, lipids, and carbohydrates)that possesses desirable physiologic characteristics for application tothe implant site or administration via a pharmaceutical compositions ofthe invention. Therapeutics include, without limitation, antiinfectivessuch as antibiotics and antiviral agents; chemotherapeutic agents (e.g.,anticancer agents); anti-rejection agents; analgesics and analgesiccombinations; anti-inflammatory agents; hormones such as steroids;growth factors (including but not limited to cytokines, chemokines, andinterleukins) and other naturally derived or genetically engineeredproteins, polysaccharides, glycoproteins and lipoproteins. These growthfactors are described in The Cellular and Molecular Basis of BoneFormation and Repair by Vicki Rosen and R. Scott Thies, published by R.G. Landes Company, hereby incorporated herein by reference. Additionaltherapeutics include thrombin inhibitors, antithrombogenic agents,thrombolytic agents, fibrinolytic agents, vasospasm inhibitors, calciumchannel blockers, vasodilators, antihypertensive agents, antimicrobialagents, antibiotics, inhibitors of surface glycoprotein receptors,antiplatelet agents, antimitotics, microtubule inhibitors, antisecretory agents, actin inhibitors, remodeling inhibitors, antisensenucleotides, anti metabolites, antiproliferatives, anticancerchemotherapeutic agents, anti-inflammatory steroids, non-steroidalanti-inflammatory agents, immunosuppressive agents, growth hormoneantagonists, growth factors, dopamine agonists, radiotherapeutic agents,peptides, proteins, enzymes, extracellular matrix components,angiotensin-converting enzyme (ACE) inhibitors, free radical scavengers,chelators, antioxidants, anti polymerases, antiviral agents,photodynamic therapy agents and gene therapy agents.

Additionally, various proteins (including short chain peptides), growthagents, chemotatic agents, growth factor receptors or ceramic particlescan be added to the foams during processing, adsorbed onto the surfaceor back-filled into the foams after the foams are made. For example, inone embodiment, the pores of the foam may be partially or completelyfilled with biocompatible resorbable synthetic polymers or biopolymers(such as collagen or elastin), biocompatible ceramic materials (such ashydroxyapatite), and combinations thereof, and may optionally containmaterials that promote tissue growth through the device. Suchtissue-growth materials include but are not limited to autograft,allograft or xenograft bone, bone marrow and morphogenic proteins.Biopolymers can also be used as conductive or chemotactic materials, oras delivery vehicles for growth factors. Examples include recombinantcollagen, animal-derived collagen, elastin and hyaluronic acid.Pharmaceutically-active coatings or surface treatments could also bepresent on the surface of the materials. For example, bioactive peptidesequences (RGD's) could be attached to the surface to facilitate proteinadsorption and subsequent cell tissue attachment.

Bioactive molecules include, without limitation, proteins, collagens(including types IV and XVIII), fibrillar collagens (including types I,II, III, V, XI), FACIT collagens (types IX, XII, XIV), other collagens(types VI, VII, XIII), short chain collagens (types VIII, X), elastin,entactin-1, fibrillin, fibronectin, fibrin, fibrinogen, fibroglycan,fibromodulin, fibulin, glypican, vitronectin, laminin, nidogen,matrilin, perlecan, heparin, heparan sulfate proteoglycans, decorin,filaggrin, keratin, syndecan, agrin, integrins, aggrecan, biglycan, bonesialoprotein, cartilage matrix protein, Cat-301 proteoglycan, CD44,cholinesterase, HB-GAM, hyaluronan, hyaluronan binding proteins, mucins,osteopontin, plasminogen, plasminogen activator inhibitors, restrictin,serglycin, tenascin, thrombospondin, tissue-type plasminogen activator,urokinase type plasminogen activator, versican, von Willebrand factor,dextran, arabinogalactan, chitosan, polyactide-glycolide, alginates,pullulan, gelatin and albumin.

Additional bioactive molecules include, without limitation, celladhesion molecules and matricellular proteins, including those of theimmunoglobulin (Ig; including monoclonal and polyclonal antibodies),cadherin, integrin, selectin, and H-CAM superfamilies. Examples include,without limitation, AMOG, CD2, CD4, CD8, C-CAM (CELL-CAM 105), cellsurface galactosyltransferase, connexins, desmocollins, desmoglein,fasciclins, F11, GP Ib-IX complex, intercellular adhesion molecules,leukocyte common antigen protein tyrosine phosphate (LCA, CD45), LFA-1,LFA-3, mannose binding proteins (MBP), MTJC18, myelin associatedglycoprotein (MAG), neural cell adhesion molecule (NCAM), neurofascin,neruoglian, neurotactin, netrin, PECAM-1, PH-20, semaphorin, TAG-1,VCAM-1, SPARC/osteonectin, CCN1 (CYR61), CCN2 (CTGF; Connective TissueGrowth Factor), CCN3 (NOV), CCN4 (WISP-1), CCN5 (WISP-2), CCN6 (WISP-3),occludin and claudin. Growth factors include, without limitation, BMP's(1-7), BMP-like Proteins (GFD-5,-7,-8), epidermal growth factor (EGF),erythropoietin (EPO), fibroblast growth factor (FGF), growth hormone(GH), growth hormone releasing factor (GHRF), granulocytecolony-stimulating factor (G-CSF), granulocyte-macrophagecolony-stimulating factor (GM-CSF), insulin, insulin-like growth factors(IGF-I, IGF-II), insulin-like growth factor binding proteins (IGFBP),macrophage colony-stimulating factor (M-CSF), Multi-CSF (II-3),platelet-derived growth factor (PDGF), tumor growth factors (TGF-alpha,TGF-beta), tumor necrosis factor (TNF-alpha), vascular endothelialgrowth factors (VEGF's), angiopoietins, placenta growth factor (PIGF),interleukins, and receptor proteins or other molecules that bind withthe aforementioned factors. Short-chain peptides include, withoutlimitation (designated by single letter amino acid code), RGD, EILDV,RGDS, RGES, RFDS, GRDGS, GRGS, GRGDTP and QPPRARI.

Tissue Culture

The at least partially degradable reticulated elastomeric matrix ofembodiments of this invention can support cell types including cellssecreting structural proteins and cells that produce proteinscharacterizing organ function. The ability of the elastomeric matrix tofacilitate the co-existence of multiple cell types together and itsability to support protein secreting cells demonstrate the applicabilityof the elastomeric matrix in organ growth in vitro or in vivo and inorgan reconstruction. In addition, the at least partially degradablereticulated elastomeric matrix may also be used in the scale up of humancell lines for implantation to the body for many applications includingimplantation of fibroblasts, chondrocytes, osteoblasts, osteoclasts,osteocytes, synovial cells, bone marrow stromal cells, stem cells,fibrocartilage cells, endothelial cells, smooth muscle cells,adipocytes, cardiomyocytes, myocytes, keratinocytes, hepatocytes,leukocytes, macrophages, endocrine cells, genitourinary cells, lymphaticvessel cells, pancreatic islet cells, muscle cells, intestinal cells,kidney cells, blood vessel cells, thyroid cells, parathyroid cells,cells of the adrenal-hypothalamic pituitary axis, bile duct cells,ovarian or testicular cells, salivary secretory cells, renal cells,epithelial cells, nerve cells, stem cells, progenitor cells, myoblastsand intestinal cells.

The approach to engineer new tissue can be obtained through implantationof cells seeded in elastomeric matrices (either prior to or concurrentto or subsequent to implantation). In this case, the elastomericmatrices may be configured either in a closed manner to protect theimplanted cells from the body's immune system, or in an open manner sothat the new cells can be incorporated into the body. Thus in anotherembodiment, the cells may be incorporated, i.e. cultured andproliferated, onto the elastomeric matrix prior, concurrent orsubsequent to implantation of the elastomeric matrix in the patient.

In one embodiment, the implantable device made from at least partiallydegradable reticulated elastomeric matrix can be seeded with a type ofcell and cultured before being inserted into the patient, optionallyusing a delivery-device, for the explicit purpose of tissue repair ortissue regeneration. It is necessary to perform the tissue or cellculture in a suitable culture medium with or without stimulus such asstress or orientation. The cells include fibroblasts, chondrocytes,osteoblasts, osteoclasts, osteocytes, synovial cells, bone marrowstromal cells, stem cells, fibrocartilage cells, endothelial cells andsmooth muscle cells.

Surfaces on the at least partially degradable reticulated elastomericmatrix possessing different pore morphology, size, shape and orientationmay be cultured with different types of cells to develop cellular tissueengineering implantable devices that are specifically targeted towardsorthopedic applications, especially in soft tissue attachment, repair,regeneration, augmentation and/or support encompassing the spine,shoulder, knee, hand or joints, and in the growth of a prosthetic organ.In another embodiment, all the surfaces on the at least partiallydegradable reticulated elastomeric matrix possessing similar poremorphology, size, shape and orientation may be so cultured.

In other embodiments, the at least partially degradable reticulatedelastomeric matrix of embodiments of this invention may haveapplications in the areas of mammary prostheses, pacemaker housings,LVAD bladders or as a tissue bridging matrix.

Compressive Molding

In addition to varying the chemistry and/or processing of degradableelastomeric matrix in order to obtain a range of desirable or targetedimplantable device performance, post-reticulation steps, such asimparting endopore features (already discussed above) can also be usedto obtain a range of desirable or targeted implantable deviceperformance. In another post-reticulation embodiment, the degradablereticulated elastomeric matrix is compressed in at least one dimension,e.g., 1-dimensional compression, 2-dimensional compression, or 3dimensional compression, in a compressive molding process and, ifreinforced with a reinforcement as discussed in detail below, remainscompressed during the inclusion of the reinforcement.

In one secondary processing method, referred to herein as compressivemolding, desirable enhanced performance is obtained by densificationand/or orientation in one dimension, two dimensions or three dimensionsusing different temperatures. In one embodiment, the densificationand/or orientation can be effected without the use of a mold. In anotherembodiment, the densification and/or orientation is facilitated by usinga mold. As discussed below, the densification and/or orientation isusually carried out at elevated temperatures above over a period of timewhere the length of time depends on the temperature(s) used. In anotherembodiment, the compressive molding process is conducted in a batchprocess. In another embodiment, the compressive molding process isconducted in a continuous process.

A “preform” is a shaped uncompressed reticulated elastomeric matrix thathas been cut or machined from a block of degradable reticulatedelastomeric matrix for use in secondary processing, such as compressivemolding. The preform can have a predetermined size and shape. In oneembodiment, the size and shape of the preform is determined by the finalor desired compression ratio that will be imparted during compressivemolding.

When a mold is used, the mold cavity can have a fixed shape, such as acylinder, cube, sphere or ellipsoid, or it can have an irregular shape.The reticulated cross-linked at least partially degradable elastomericpolycaprolactone urea-urethane matrix, upon being compressive molded,conforms to a great degree to the geometry of the mold at the end of thedensification and/or orientation step.

Compressive molding can also be carried out in a mold the contours ofwhich can change during the compressive molding process, e.g., from aninitial shape and/or size to a final shape and/or size. The change inthe dimension of this mold can be initiated or activated by applicationof heat or application of load. In one such example, acylindrically-shaped preform of degradable reticulated elastomericmatrix having diameter d3 can be placed inside a thin-walled PTFE(polytetrafluoroethylene) shrink-wrap tube having initial diameter, d1,greater than d3. Upon application of external heat and/or load, the PTFEshrink-wrap tube can shrink from its initial diameter d1 to a smallerfinal diameter of d2. The cylindrical preform with diameter d3 can becompressed to a final diameter substantially equal to or equal to d2.The compressed degradable reticulated elastomeric matrix can conform toa great degree to the geometry of the mold which, in this embodiment, isthe heat-shrunk PTFE tubing.

In one embodiment, the densification and/or orientation believed to beimparted to the reticulated elastomeric matrix by compressive moldingresults in property enhancement and/or performance enhancement for thecompressed reticulated elastomeric matrix, such as in its mechanicalproperties, e.g., tensile strength, tensile modulus, compressivestrength, compressive, modulus and/or tear strength. In anotherembodiment, the densification and/or orientation believed to be impartedto the reticulated elastomeric matrix by compressive molding results inperformance enhancement related to delivery, conformability, handlingand/or filling at the tissue healing site.

During compressive molding, in one embodiment at least one dimension ofthe preform, e.g., the length and/or diameter of a cylindrical preform,is reduced in size. In another embodiment, during compressive moldingone dimension of a preform, such as the thickness dimension of a cube,is reduced while its other two dimensions remain substantiallyunchanged. During this compressive molding process, each face isbelieved to be approximately motionless or fixed relative to the outsidesurface of the preform in contact with a face as the faces are pushedcloser together; therefore, this process of compressive molding can alsobe described as a “fixed mold wall” compressive molding process.

In another embodiment, substantially all of the changes in preformvolume occurring upon compressive molding can be accounted for by thedimensional change occurring only in one dimension. In anotherembodiment, all of the changes in preform volume occurring uponcompressive molding can be accounted for by the dimensional changeoccurring only in one dimension. In another embodiment, substantiallyall of the changes in preform volume occurring upon compressive moldingcan be accounted for by the dimensional change occurring only in thethickness dimension.

The linear compression ratio, defined herein as the ratio of theoriginal magnitude of the dimension that is reduced during compressivemolding to the magnitude of the final dimension after compressivemolding, is from about 1.15 to about 9.0. In another embodiment, thelinear compression ratio is from about 2.5 to about 7.0. In anotherembodiment, the linear compression ratio is from about 2.0 to about 6.0.

If the reduction in the dimension that is reduced during compressivemolding is expressed in terms of linear compressive strain, i.e., thechange in a dimension over that original dimension, the linearcompressive strain is from about 15% to about 90%. In anotherembodiment, the linear compressive strain is from about 25% to about90%. In another embodiment, the linear compressive strain is from about30% to about 85%. In another embodiment, the linear compressive strainis from about 40% to about 75%.

In another embodiment, during compressive molding the radius dimensionof a cylindrical preform is reduced, i.e., the circumference is reduced,such that the dimensional reduction occurs in two directions, while, inthe other direction, the cylinder's height remains substantiallyunchanged. In another embodiment, during compressive molding the radiusdimension of a cylindrical preform is reduced, while, in the otherdirection, the cylinder's height remains unchanged.

In another embodiment, substantially all of the changes in preformvolume occurring upon compressive molding can be accounted for by thedimensional change occurring only in two dimensions. In anotherembodiment, all of the changes in preform volume occurring uponcompressive molding can be accounted for by the dimensional changeoccurring only in two dimensions. In another embodiment, substantiallyall of the changes in preform volume occurring upon compressive moldingcan be accounted for by the dimensional change occurring only in theradial dimension. In another embodiment, all of the changes in preformvolume occurring upon compressive molding can be accounted for by thedimensional change occurring only in the radial dimension.

The radial compression ratio, defined herein as the ratio of theoriginal magnitude of the cylindrical preform's radius to the magnitudeof the final radius after compressive molding, can be from about 1.2 toabout 6.7. In another embodiment, the radial compression ratio is fromabout 1.5 to about 6.0. In another embodiment, the radial compressionratio is from about 2.5 about 6.0. In another embodiment, the radialcompression ratio is from about 2.0 to about 5.0.

In another embodiment, the cross-sectional compression ratio, definedherein as the ratio of the original magnitude of the cylindricalpreform's cross-sectional area to the magnitude of the finalcross-sectional area after compressive molding, is from about 1.5 toabout 47. In another embodiment, the cross-sectional compression ratiois from about 1.5 to about 25. In another embodiment, thecross-sectional compression ratio is from about 2.0 to about 9.0. Inanother embodiment, the cross-sectional compression ratio is from about2.0 to about 7.0.

If the reduction in the cross-sectional area during compressive moldingof a cylindrical preform is expressed in terms of cross-sectionalcompressive strain, i.e., the change in a cross-sectional area over thatoriginal cross-sectional area, the cross-sectional compressive straincan be from about 25% to about 90%. In another embodiment, thecross-sectional compressive strain is from about 33% to about 90%. Inanother embodiment, the cross-sectional compressive strain is from about50% to about 88%.

Compressive molding of the at least partially degradable reticulatedelastomeric matrix materials of the present invention is conducted attemperatures above 25° C. and can be carried out from about 80° C. toabout 150° C. in one embodiment, from about 100° C. to about 150° C. inanother embodiment, or from about 110° C. to about 145° C. in anotherembodiment. In another embodiment, as the temperature at which thecompressive molding process is carried out increases, the time at whichthe compressive molding process is carried out decreases. The time forcompressive molding is usually from about 10 seconds to about 10 hours.In another embodiment, the compressive molding time is from about 30seconds to about 5 hours. In another embodiment, the compressive moldingtime is from about 30 seconds to about 3 hours. As the temperature atwhich the compressive molding process is conducted is raised, the timefor compressive molding decreases. At higher temperatures, the time forcompressive molding must be short, as a long compressive molding timemay cause the degradable reticulated elastomeric matrix to thermallydegrade. For example, in one embodiment, at temperatures of about 140°C., the time for compressive molding is about 30 minutes or less in oneembodiment, about 10 minutes or less in another embodiment, or about 5minutes or less in another embodiment. In another embodiment, at atemperature of about 130° C., the time for compressive molding is about60 minutes or less in one embodiment, about 20 minutes or less inanother embodiment, or about 10 minutes or less in another embodiment.In another embodiment, at temperatures of about 110° C., the time forcompressive molding is about 240 minutes or less in one embodiment,about 120 minutes or less in another embodiment, or about 30 minutes orless in another embodiment.

After compressive molding, the permeability of the compressed degradablereticulated elastomeric matrix usually decreases and, thereby,potentially reduces the ability of the compressed degradable reticulatedelastomeric matrix to provide for tissue ingrowth and proliferation.Therefore, it is important to maintain good fluid permeability aftercompressive molding even after the cross-sectional area is reduced byabout 50% or in in another embodiment, the cross-sectional area isreduced by about 60% or in another embodiment, the cross-sectional areais reduced by about 80%.

Reinforcement Incorporation

Degradable elastomeric matrix can undergo a further post-reticulationprocessing step or steps, in addition to reticulation, imparting endporefeatures and compressive molding already discussed above. For example,in another embodiment, the degradable reticulated elastomeric matrix isreinforced with a reinforcement to create composite mesh comprisingdegradable reticulated elastomeric matrix. In this case, the compsitemesh comprises at least one functional element, i.e. the reinforcement,designed to enhance the mechanical load bearing functions such asstrength, stiffness, tear resistance, burst strength, suture pull outstrength etc. In other embodiments, the reinforcement is in at least onedimension, e.g., a 1 dimensional reinforcement (such as a fiber), a2-dimensional reinforcement (such as a 2-dimensional mesh made up ofintersecting 1 dimensional reinforcement elements), or a 3 dimensionalreinforcement (such as a 3-dimensional grid). In other embodiments, thereinforcement is a medical grade textile.

The reinforced elastomeric matrix and/or composite mesh comprisingdegradable reticulated elastomeric matrix can be made more functionalfor specific uses in various implantable devices by including orincorporating a reinforcement, e.g., fibers, into the degradablereticulated cross-linked elastomeric urea-urethane matrix. In oneembodiment elastomeric matrix is compressed. The enhancedfunctionalities that can be imparted by using a reinforcement includebut are not limited to enhancing the ability of the device to withstandpull out loads associated with suturing during surgical procedures, thedevice's ability to be positioned at the repair site by suture anchorsduring a surgical procedure, and holding the device at the repair siteafter the surgery when the tissue healing takes place. In anotherembodiment, the enhanced functionalities provide additional load bearingcapacities to the device during surgery in order to facilitate therepair or regeneration of tissues. In another embodiment, the enhancedfunctionalities provide additional load bearing capacities to thedevice, at least through the initial days following surgery, in order tofacilitate the repair or regeneration of tissues. In another embodiment,the enhanced functionalities provide additional load bearing capacitiesto the device following surgery in order to facilitate the repair orregeneration of tissues. In one embodiment, the reinforcement used doesnot interfere with the matrix's capacity to accommodate tissue ingrowthand proliferation.

One way of obtaining enhanced functionalities is by incorporating areinforcement, e.g., fibers, fiber meshes, wires and/or sutures, intothe elastomeric matrix. Another exemplary way of obtaining enhancedfunctionalities is by reinforcing the matrix with at least onereinforcement. The incorporation of the reinforcement into the matrixcan be achieved by various ways, including but not limited use of anadhesive such as silicone, polyurethanes, permanent polymers andpreferably biodegradable polymers. Exemplary biodegradable polymers thatcan be used as adhesives include not limited to copolymers ofpolycaprolactone, polylactic acid, polyglycolic acid, acid d-, l- andmeso lactide and poly para-dioxanone, etc. or mixtures thereof. Inanother embodiment, biodegradable polymers that can be used as adhesivescomprise copolymers of caprolactone with polylactic acid, polyglycolicacid, acid d-, l- and meso lactide and poly para-dioxanone, etc. ormixtures thereof. Exemplary polyurethane that can be used as adhesivesinclude not limited to polycarbonate polyurethanes, polysiloxanepolyurethanes, poly(siloxane-co-ether) polyurethanes, polycarbonatepolysiloxane polyurethanes, polycarbonate urea-urethanes, polycarbonatepolysiloxane urea-urethanes and the like and their mixtures.

The adhesive can be applied between the reinforcement and elastomericmatrix and cured. In another embodiment, the adhesive can be appliedeither to reinforcement or the elastomeric matrix or both before beingcured. The adhesive can be applied by dip or spray coating, painted witha brush, by use of customized coating fixtures that can lay down ordeliver a thin layer of adhesive using blades with adjustable heightsfollowed by transfer of the thin layer of adhesive on to thereinforcement or the elastomeric matrix. Or both. In one embodiment, theadhesive is a solution and the polymer content in the adhesive solutionis from about 1% to about 40% by weight. In another embodiment, thepolymer content in the adhesive solution is from about 1% to about 20%by weight. In another embodiment, the polymer content in the adhesivesolution is from about 1% to about 10% by weight. In one embodiment, theadhesive does not contain any solvents. The solvent or solvent blend forthe coating solution is chosen, e.g., based on the considerationsdiscussed in the previous section (i.e., in the “Imparting EndoporeFeatures” section). In one embodiment, the adhesive can be cured between50° C. and 150° C. and in another embodiment between 60° C. and 120° C.In one embodiment, the adhesive can be cured between 10 minutes and 3hours and in another embodiment between 15 minutes and 2 hours.

The adhesive can be applied between the reinforcement and elastomericmatrix by melt-bonding the adhesive the reinforcement and elastomericmatrix. In another embodiment, the adhesive can be applied either toreinforcement or the elastomeric matrix. In another embodiment, theadhesive may be applied by melting the film-forming adhesive polymer andapplying the melted polymer through a die, in a process such asextrusion or coextrusion, as a thin layer of melted. In theseembodiments, the melted polymer either coats the reinforcement or coatsthe elastomeric matrix macro surface but does not penetrate into theinterior to any significant depth or bridges or plugs pores of thatsurface. Thus, the reticulated nature of portions of the elastomericmatrix removed from the macro surface, and portions of the elastomericmatrix's macro surface not in contact with the melted polymer, ismaintained. Upon applying pressure to create contact between elastomericmatrix and reinforcement, cooling and solidifying, the melted polymerforms a layer of solid coating on the elastomeric matrix and thereinforcement and in the interface between them. In one embodiment, theprocessing temperature of the melted thermoplastic adhesive polymer isat least about 60° C. In another embodiment, the processing temperatureof the melted thermoplastic adhesive polymer is at least above about 90°C. In another embodiment, the processing temperature of the meltedthermoplastic adhesive polymer is at least above about 120° C. and inyet another embodiment, the processing temperature of the meltedthermoplastic adhesive polymer is at least above about 140° C. The meltcan be applied by extruding or coextruding or injection molding orcompression molding or compressive molding the melt onto the degradablereticulated elastomeric matrix.

Embodiments of the invention composite mesh comprising degradablereticulated elastomeric include a “sandwich design” wherein thereinforcement can be incorporated between two layers of the elastomericmatrix, and an “open face sandwich design” wherein the medical gradetextile is incorporated with a single layer of elastomeric matrix. Inanother embodiment, multiple layers of reinforcement and elastomericmatrix can be stacked in an alternating fashion and an adhesive can beused to incorporate the alternating layer. Without being bound by anyparticular theory, too little adhesive may prevent adequate bondingwhile too much adhesive may lad to partial or full clogging of the poresof the degradable reticulated elastomeric matrix or can also lead toloss of flexibility during delivery and placement.

The elastomeric matrix that incorporates the fibers into the degradablereticulated cross-linked partially degradable and fully degradableelastomeric polycarbonate urea-urethane matrix can vary in itsorientation. Orientation can occur during initial formation of foam,during reticulation, or during secondary processing that may occur afterreticulation and thermal curing of the foam. The results of orientationare manifested by enhanced properties and/or enhanced performance in thedirection of orientation. In one embodiment, a device made from areinforced degradable reticulated elastomeric matrix is positioned inthe tissue being repaired in such a way that the enhanced propertiesand/or enhanced performance of the oriented matrix is aligned in thedirection to resist the higher load bearing direction. Incorporation ofthe reinforcement may lead to enhanced performance of the matrix, whichis superior to that which would be obtained by orienting the reinforcedmatrix in one or more directions.

The reinforcement can comprise mono-filament fiber, multi-filament yarn,braided multi-filament yarns, commingled mono-filament fibers,commingled multi-filament yarns, bundled mono-filament fibers, bundledmulti-filament yams, and the like. The reinforcement can comprise anamorphous polymer, semi-crystalline polymer, e.g., polyester or nylon,carbon, e.g., carbon fiber, bio-glass, glass, e.g., glass fiber,ceramic, cross-linked polymer fiber and the like or any mixture thereof.The fibers can be made from absorbable or non-absorbable materials. Inone embodiment, the fiber reinforcement of the present invention is madefrom a biocompatible material(s).

In one embodiment, the reinforcement can be made from at least onenon-absorbable material, such as a non-biodegradable or non-absorbablepolymer. Examples of suitable non-absorbable polymers include but arenot limited to polyesters, polyolefins and blends thereof as well as,polyamides; polycarbonates; polyoxymethylenes; polyimides; polyethers;epoxy resins; polyurethanes; and any mixture thereof.

In another embodiment, the reinforcement can be made preferably from atleast one biodegradable, bioabsorbable or absorbable polymer. Examplesof suitable absorbable polymers include but are not limited to aliphaticpolyesters, e.g., homopolymers and copolymers of lactic acid, glycolicacid, lactide, glycolide, para-dioxanone, trimethylene carbonate,ε-caprolactone and blends thereof. Further exemplary biocompatiblepolymers include film-forming bioabsorbable polymers such as aliphaticpolyesters, poly(amino acids), copoly(ether-esters), polyalkylenesoxalates, polyamides, poly(iminocarbonates), polyorthoesters,polyoxaesters including polyoxaesters containing amido groups,polyamidoesters, polyanhydrides, polyphosphazenes, biomolecules, and anymixture thereof. Aliphatic polyesters, for the purpose of thisapplication, include polymers and copolymers of lactide (which includeslactic acid d-, l- and meso lactide), ε-caprolactone, glycolide(including glycolic acid), hydroxybutyrate, hydroxyvalerate,para-dioxanone, trimethylene carbonate (and its alkyl derivatives),1,4-dioxepan-2-one, 1,5-dioxepan-2-one, 6,6-dimethyl-1,4-dioxan-2-one,and any mixture thereof.

Such fiber(s)/yam(s) can be made by melt extrusion, melt extrusionfollowed by annealing and stretching, solution spinning, electrostaticspinning, and other methods known to those in the art. Each fiber can bebi-layered, with an inner core and an outer sheath, or multi-layered,with inner core, an outer sheath and one or more intermediate layers. Inbi- and multi-layered fibers, the core, the sheath or any layer(s)outside the core can comprise a degradable or dissolvable polymer. Thefibers can be uncoated or coated with a coating that can comprise anamorphous polymer, semi-crystalline polymer, carbon, glass, ceramic, andthe like or any mixture thereof.

The reinforcement can be made from carbon, glass, a ceramic,bioabsorbable glass, silicate-containing calcium-phosphate glass, or anymixture thereof. The calcium-phosphate glass, the degradation and/orabsorption time in the human body of which can be controlled, cancontain metals, such as iron, magnesium, sodium, potassium, or anymixture thereof.

In another embodiment, the 1-dimensional reinforcement and 2-dimensionalreinforcement comprises intersecting 1 dimensional reinforcementelements comprises an amorphous polymer fiber, a semi-crystallinepolymer fiber, a cross-linked polymer fiber, a biopolymer fiber, acollagen fiber, an elastin fiber, carbon fiber, glass fiber,bioabsorbable glass fiber, silicate-containing calcium-phosphate glassfiber, ceramic fiber, polyester fiber, nylon fiber, an amorphous polymeryarn, a semi-crystalline polymer yarn, a cross-linked polymer yarn, abiopolymer yarn, a collagen yarn, an elastin yarn, carbon yarn, glassyarn, bioabsorbable glass yarn, silicate-containing calcium-phosphateglass yam, ceramic yarn, polyester yarn, nylon yarn, or any mixturethereof.

The reinforcement can be incorporated into the degradable reticulatedelastomeric matrix in different patterns. In one embodiment, thereinforcement is placed along the entire surface or the contact surfaceof the elastomeric matrix. In one embodiment, the reinforcement isplaced along the border of the device, maintaining a fixed distance fromthe device's edges. In another embodiment, the reinforcement is placedalong the border of the device, maintaining a variable distance from thedevice's edges. In another embodiment, the reinforcement is placed alongthe perimeter, e.g., circumference for a circular device, of the device,maintaining a fixed distance from the device's edges. In anotherembodiment, the reinforcement is placed along the perimeter of thedevice, maintaining a variable distance from the device's edges. Inanother embodiment, the reinforcement is present as a plurality ofparallel and/or substantially parallel 1 dimensional reinforcementelements, e.g., as a plurality of parallel lines such as parallelfibers. In another embodiment, the reinforcement is placed as a 2- or 3dimensional reinforcement grid in which the 1 dimensional reinforcementelements cross each other's path. In another embodiment, thereinforcement is placed as a 2- or 3 dimensional reinforcement grid inwhich the 1 dimensional reinforcement elements cross each other's pathand there is no special reinforcement along the perimeter or the border.The grid can have one or multiple reinforcement elements. In 2- or 3dimensional reinforcement grid embodiments, the elements of thereinforcement can be arranged in geometrically-shaped patterns, such assquare, rectangular, trapezoidal, triangular, diamond, parallelogram,circular, eliptical, pentagonal, hexagonal, and/or polygons with sevenor more sides. The reinforcement elements comprising a reinforcementgrid can all be of the same shape and size or can be of different shapesand sizes. The reinforcement elements comprising a reinforcement gridcan additionally include border, perimeter and/or parallel lineelements. The performance or properties of the reinforcement gridincorporates the reinforcement into the matrix and the thus-reinforcedmatrix depends on the inherent properties of the reinforcement as wellas the pattern, geometry and number of elements of the grid.

In other embodiments, the clearance or spacing between reinforcementelements, such as the clearance between adjacent linear reinforcementelements, can be from about 0.25 mm to about 20 mm in one embodiment, orfrom about 0 5 mm to about 15 mm in another embodiment. In otherembodiments, the clearance between reinforcement elements issubstantially the same between elements. In other embodiments, theclearance between reinforcement elements differs between differentelements. In other multi-dimensional reinforcement embodiments, theclearance between reinforcement elements in one dimension is independentof the clearance(s) between reinforcement elements in any otherdimension.

The diameter of a reinforcement element having a substantially circularcross-section can be from about 0.03 mm to about 0.50 mm in oneembodiment, or from about 0.07 mm to about 0.30 mm in anotherembodiment, or from about 0.05 mm to about 1 0 mm in another embodiment,or from about 0.03 mm to about 1.0 mm in another embodiment. In anotherembodiment, the diameter of a reinforcement element having asubstantially circular cross-section can be equivalent to a USP suturediameter from about size 8 0 to about size 0 in one embodiment, fromabout size 8 0 to about size 2 in another embodiment, from about size 80 to about size 2-0 in another embodiment.

The reinforcement layout or the distribution and pattern ofreinforcement elements, e.g., fibers or sutures or grid in the matrixwill depend on design requirement and/or the application for which thedevice will be used.

In one embodiment, the incorporation of the reinforcement into thematrix can be achieved by various ways, including but not limited tostitching, sewing, weaving and knitting. In one embodiment, theattachment of the reinforcement to the matrix can be through a sewingstitch. In another embodiment, the attachment of the reinforcement tothe matrix can be through a sewing stitch that includes an interlockingfeature. In another embodiment, the incorporation of the reinforcementinto the matrix can be achieved by foaming of the elastomeric matrixingredients around a pre-fabricated or pre-formed reinforcement elementmade from a reinforcement and reticulating the composite structurethus-formed to create an intercommunicating and interconnected porestructure. In one embodiment, the reinforcement used does not interferewith the matrix's capacity to accommodate tissue in-growth andproliferation. In an embodiment where sewing is used to incorporate thereinforcement into the matrix, the pitch of the stitch, i.e., thedistance between successive stitches or attachment points within thesame line, is from about 0.25 mm to about 4 mm in one embodiment or fromabout 1 mm to about 3 mm in another embodiment.

For a device of this invention comprising a reinforced degradablereticulated elastomeric matrix, the maximum dimension of anycross-section perpendicular to the device's thickness is from about 0.25mm to about 100 mm in one embodiment. In another embodiment, the maximumthickness of the device is from about 0.25 mm to about 20 mm. Thecomposite mesh comprising degradable reticulated elastomeric matrix orcomposite surgical mesh comprising degradable reticulated elastomericmatrix can be made available in various sizes. In certain embodiments ofthe composite mesh device comprising degradable reticulated elastomericmatrix or composite surgical mesh device comprising degradablereticulated elastomeric matrix can range from about 0 5 mm to about 4 mmin thickness and may be in any two-dimensional or three-dimensionalshape. Exemplary embodiments of a two-dimensional shape may includeregular and irregular shapes, such as, for example, triangular,rectangular, circular, oval, elliptical, trapezoidal, pentagonal,hexagonal and irregular configurations, including one that correspondsto the shape of the defect, and other shapes. Exemplary embodiments of athree-dimensional shape may include, plugs, cylinders, tubularstructures, stent-like structures, and other configurations, includingone that corresponds to the contours of the defect, and otherconfigurations. The device may have a major axis having a length betweenabout 2 cm to about 50 cm. The device may be in a square shape with aside having a length between about 2 cm to about 50 cm.

In one embodiment, the implantable device and/or its reinforcement canbe coated with one or more bioactive molecules, such as the plateletrich plasma, proteins, collagens, elastin, entactin-1, fibrillin,fibronectin, cell adhesion molecules, matricellular proteins, cadherin,integrin, selectin, H-CAM superfamilies, and the like described indetail herein.

Example 1 Synthesis and Properties of Degradable Reticulated ElastomericMatrix Containing Polycaprolactone Polyol

A reticulated partially resorbable elastomeric matrix was made by thefollowing procedure: The aromatic isocyanate MONDUR 1488 (from BayerMaterial Science) was used as the isocyanate component. MONDUR 1488 is aliquid at 25° C. MONDUR 1488 contains 4,4′-diphenylmethane diisocyanate(4,4 MDI) and 2,4′-diphenylmethane diisocyanate (2,4 MDI) and has anisocyanate functionality of about 2.2 to 2.3. The ratio of (4,4 MDI) to2,4-MDI) is approximately 2.5:1. A polycaprolactone diol with amolecular weight of about 2,000 Daltons was used as the polyol componentand was a solid at 25° C. Distilled water was used as the blowing agent.The catalysts used were the amines triethylene diamine (33% by weight indipropylene glycol; DABCO 33LV from Air Products) andbis(2-dimethylaminoethyl)ether (23% by weight in dipropylene glycol;NIAX A-133 from Momentive Performance Chemicals). Silicone-basedsurfactants TEGOSTAB BF 2370, TEGOSTAB B5055, AND TEGOSTAB B8300 (fromEvonik Degussa) were used for cell stabilization. A cell-opener was used(ORTEGOL 501 from Evonik Degussa). Glycerine (99.7% USP Grade) and1,4-butanediol (99.75% by weight purity, from Lyondell) were added tothe mixture as, respectively, a cross-linking agent and a chainextender: The proportions of the ingredients that were used is given inTable II below.

TABLE II Ingredient Parts by Weight Polyol Component 100.00 IsocyanateComponent 45.58 Isocyanate Index 1.00 Cell Opener 3.00 Distilled Water1.60 BF2370 Surfactant 1.20 B8300 Surfactant 0.60 B5055 Surfactant 0.6033LV Catalyst 0.40 A-133 Catalyst 0.15 Glycerine 1.00 1,4-Butanediol1.50

The isocyanate index, is the mole ratio of the number of isocyanategroups in a formulation available for reaction to the number of hydroxylgroups in the formulation that are able to react with those isocyanategroups, e.g., the reactive groups of diol(s), polyol component(s), chainextender(s), water and the like, when present. As seen above, theisocyanate index was low and equal to 1.0; a stoichiometrically balancedratio of isocyanate and hydroxyl groups was used to prevent formation ofisocyanurate likages, biuret linkages and allophanate linkages. Theisocyanate component of the formulation was placed into the component Ametering system of an Edge Sweets Bench Top model urethane mixingapparatus and maintained at a temperature of about 20-25° C.

The polyol was liquefied at about 70° C. in an oven and combined withthe cell opener in the aforementioned proportions to make a homogeneousmixture. This mixture was placed into the component B metering system ofthe Edge Sweets apparatus. This polyol component was maintained in thecomponent B system at a temperature of about 65-70° C.

The remaining ingredients consisting of the chain extender,cross-linker, cell opener, catalysts, surfactants from Table 1 weremixed in the aforementioned proportions into a single homogeneous batchand placed into the component C metering system of the Edge Sweetsapparatus. This component was maintained at a temperature of about20-25° C. During foam formation, the ratio of the flow rates, in gramsper minute, from the supplies for component A:component B: component Cwas about 5:10:1.

The above components were combined in a continuous manner in the 250 ccmixing chamber of the Edge Sweets apparatus that was fitted with a 10 mmdiameter nozzle placed below the mixing chamber. Mixing was promoted bya high-shear pin-style mixer operating in the mixing chamber. The mixedcomponents exited the nozzle into a rectangular cross-sectionrelease-paper coated mold. Thereafter, the foam rose to substantiallyfill the mold. The resulting mixture began creaming about 10 secondsafter contacting the mold and was at full rise within 120 seconds. Thetop of the resulting foam was trimmed off and the foam was allowed tocure at ambient temperature for 24 hours. FIG. 2 is a scanning electronmicrograph (SEM) image of un-reticulated degradable elastomeric matrix 1after foaming and ambient curing. It demonstrates a collection of cellswhose walls though showing some pores do not show that the cells areinterconnected via the open pores. It is porous with a few open poresbut does not have the inter-connected nature or possess the possibilityof inter communication between the cells that are far from each other.

Following curing, the sides and bottom of the foam block were trimmedoff then the foam was placed into a reticulator device comprising apressure chamber, the interior of which was isolated from thesurrounding atmosphere. The pressure in the chamber was reduced so as toremove substantially all the air in the cured foam. A mixture ofhydrogen and oxygen gas, present at a molar ratio of 2.3:1 of Hydrogento Oxygen, sufficient to support combustion, was introduced or chargedinto the chamber. A mixture of hydrogen and oxygen gas, present at aratio of 2.3:1 H₂:O₂, sufficient to support combustion, was charged intothe chamber. The pressure in the chamber was maintained aboveatmospheric pressure for a sufficient time to ensure gas penetrationinto the foam. The gas in the chamber was then ignited by a spark plugand the ignition exploded the gas mixture within the foam. To minimizecontact with any combustion products and to cool the foam, the resultingcombustion gases were removed from the chamber and replaced with about25° C. nitrogen immediately after the explosion. Then, theabove-described reticulation process was repeated one more time. Withoutbeing bound by any particular theory, the explosions were believed tohave at least partially removed or more likely substantially removedmany of the cell walls or “windows” between adjoining cells in the foam,thereby creating inter-connected cells via open pores and leading to areticulated elastomeric matrix structure.

The average cell diameter or other largest transverse dimension ofDegradable Reticulated Elastomeric Matrix 1, as determined from opticalmicroscopy observations, was about 3.79 μm. FIG. 3 is a scanningelectron micrograph (SEM) image of Reticulated Elastomeric Matrix 1demonstrating, e.g., the network of cells interconnected via the openpores therein and the communication and interconnectivity thereof. Thecells from different regions in the scans are interconneted and cancommunicate with each other for fluid flow or tissue ingrowth; the thenetwork of interconnected cells creates a continuous void phase. Thescale bar at the bottom edge of FIG. 10 corresponds to about 1000 μm.

The following tests were carried out on the thus-formed DegradableReticulated Elastomeric Matrix, obtained from reticulating the foam,using test methods based on ASTM Standard D3574. Bulk density wasmeasured using Reticulated Elastomeric Matrix 1 specimens of dimensions5.0 cm×5.0 cm×2.5 cm. The post-reticulation density was calculated bydividing the weight of the specimen by the volume of the specimen. Adensity value of 3.2 lbs/ft³ (0.051 g/cc) was obtained.

Tensile tests were conducted on Reticulated Elastomeric Matrix 1specimens that were cut either parallel to or perpendicular to thefoam-rise direction. The dog-bone shaped tensile specimens were cut fromblocks of reticulated elastomeric matrix. Each test specimen measuredabout 1.25 cm thick, about 2.54 cm wide, and about 14 cm long. The gagelength of each specimen was 3.5 cm and the gage width of each specimenwas 6.5 mm. Tensile properties (tensile strength and elongation atbreak) were measured using an INSTRON Universal Testing Instrument Model3342 with a cross-head speed of 50 cm/min (19.6 inches/min). The averagepost-reticulation tensile strength parallel to the foam-rise directionwas determined to be about 43 psi (30,230 kg/m²). The post-reticulationelongation to break parallel to the foam-rise direction was determinedto be about 246%. The average post-reticulation tensile strengthperpendicular to the foam-rise direction was determined to be about 31psi (21,790 kg/m²). The post-reticulation elongation to breakperpendicular to the foam-rise direction was determined to be about278%.

Compressive tests were conducted using Reticulated Elastomeric Matrix 1specimens measuring 5.0 cm×5.0 cm×2.5 cm. The tests were conducted usingan INSTRON Universal Testing Instrument Model 1122 with a cross-headspeed of 1 cm/min (0.4 inches/min) The post-reticulation compressivestrength at 50% compression, parallel to the foam-rise direction, wasdetermined to be about 0.4 psi (281 kg/m²).

The static recovery of Reticulated Elastomeric Matrix 1 was measured bysubjecting cylindrcular specimens, each 12 mm in diameter and 6 mm inthickness, to a 50% uniaxial compression in the foam-rise directionusing the standard compressive fixture in a Q800 Dynamic MechanicalAnalyzer (TA Instruments, New Castle, Del.) for 120 minutes followed by120 minutes of recovery time. The time required for recovery to 90% ofthe specimen's initial thickness of 6 mm (“t-90%”) was measured and theaverage determined to be 6 seconds. The time required for recovery to90% of the specimen's initial thickness of 6 mm (“t-95%”) was measuredand the average determined to be 44 seconds.

Fluid, e.g., liquid, permeability through of reticulated degradableelastomeric was measured in the foam-rise direction using the methoddescribed in Example 2. and was determined to have an average of 345Darcy. The thermal reticulation led to higher permeability brought aboutby the presence of a continuous void phase which itself is a result thenetwork of cells interconnected via the open pores therein and thesubsequent communication and interconnectivity.

Example 2 Synthesis and Properties of Degradable Reticulated ElastomericMatrix Containing Polycaprolactone Polyol

A reticulated partially resorbable elastomeric matrix was made by thefollowing procedure: The aromatic isocyanate MONDUR 1488 (from BayerMaterial Science) was used as the isocyanate component. MONDUR 1488 is aliquid at 25° C. MONDUR 1488 contains 4,4′-diphenylmethane diisocyanate(MDI) and 2,4′-MDI and has an isocyanate functionality of about 2.2 to2.3. A polycaprolactone diol, POLY-T220 from Arch Chemicals, with amolecular weight of about 2,000 Daltons, was used as the polyolcomponent and was a solid at 25° C. Distilled water was used as theblowing agent. The catalysts used were the amines triethylene diamine(33% by weight in dipropylene glycol; DABCO 33LV from Air Products) andbis(2-dimethylaminoethyl)ether (23% by weight in dipropylene glycol;NIAX A-133 from Momentive Performance Chemicals). Silicone-basedsurfactants TEGOSTAB BF 2370, TEGOSTAB B5055, AND TEGOSTAB B8300 (fromEvonik Degussa) were used for cell stabilization. A cell-opener was used(ORTEGOL 501 from Evonik Degussa). Glycerine (99.7% USP Grade) and1,4-butanediol (99.75% by weight purity, from Lyondell) were added tothe mixture as, respectively, a cross-linking agent and a chainextender. The proportions of the ingredients that were used is given inTable III below.

TABLE III Ingredient Parts by Weight Polyol Component 100.00 IsocyanateComponent 45.58 Isocyanate Index 1.00 Cell Opener 3.00 Distilled Water1.60 BF2370 Surfactant 1.20 B8300 Surfactant 0.60 B5055 Surfactant 0.6033LV Catalyst 0.40 A-133 Catalyst 0.15 Glycerine 1.00 1,4-Butanediol1.50

The isocyanate index, is the mole ratio of the number of isocyanategroups in a formulation available for reaction to the number of hydroxylgroups in the formulation that are able to react with those isocyanategroups, e.g., the reactive groups of diol(s), polyol component(s), chainextender(s), water and the like, when present. As seen above, theisocyanate index was low and equal to 1.0; a stoichiometrically balancedratio of isocyanate and hydroxygroups was used to prevent formation ofisocyanurate likages, biuret linkages and allophanate linkages.

The polyol component was liquefied at 70° C. in a circulating-air oven,and 300 g thereof was weighed out into a polyethylene cup. The remainingingredients excluding the isocyante and consisting of the chainextender, cross-linker, cell opener, catalysts, surfactants from Table 2were added to the polyol component at their proportional weights basedon the aforementioned formulation. These components were mixed togetherwith a pin style high sheer mixer attached to a motor for 60 seconds.

The required amount of isocyante was weighed into a polyethylene cup andthen added to the polyol mixture during high speed mixing. The totalformulation was mixed vigorously with the drill mixer as described abovefor 10 seconds then poured into a cardboard box with its inside surfacescovered by polyethylene coated paper. The foaming profile was asfollows: 10 seconds mixing time, 25 seconds cream time, and 90 secondsrise time. The block was allowed to cure for 24 hours at ambientconditions.

The average cell diameter or other largest transverse dimension ofDegradable Reticulated Elastomeric Matrix, as determined from opticalmicroscopy observations, was about 759 μm. The following tests werecarried out on the thus-formed Degradable Reticulated ElastomericMatrix, obtained from reticulating the foam, using test methods based onASTM Standard D3574. Bulk density was measured using DegradableReticulated Elastomeric Matrix specimens of dimensions 5.0 cm×5.0 cm×2.5cm. The post-reticulation density was calculated by dividing the weightof the specimen by the volume of the specimen. A density value of 3.60lbs/ft³ (0.058 g/cc) was obtained.

Fluid, e.g., liquid, permeability through of un-reticulated degradableelastomeric matrix 1 after foaming and ambient curing was measured inthe foam-rise direction using a Porous Materials Inc. Automated LiquidPermeameter (Model LP-101-A, Serial No. 2162006-1489). The cylindricalun-reticulated degradable elastomeric matrix specimens tested werebetween 7.0-7.0 mm in diameter and 13 mm in length or thickness. Thesample was crushed by putting one end of the the cylindrical testspeciment on a flat surface, placing a flat steel plate on top of theother cylindrical end and pushing the upper flat steel plate verticallydown and bringing it up at least 5 times. The upper plate was pushed allthe way down till the unreticulated matrix was flat. After the crushingoperation, A flat end of a specimen was placed in the center of aStainless steel sample holder with opening diameter of 6.37 mm that wasplaced at the bottom of the Liquid Permeaeter apparatus. To measureliquid permeability, water was allowed to extrude upward, driven bypressure from a fluid reservoir, from the specimen's end through thespecimen along its axis. The operations associated with permeabilitymeasurements were fully automated and controlled by a Capwin AutomatedLiquid Permeameter (version 6.71.92) which, together with MicrosoftExcel software, performed all the permeability calculations. Thepermeability of Reticulated Elastomeric Matrix using water wasdetermined to be 15 Darcy in the foam-rise direction.

Following curing, the sides and bottom of the foam block were trimmedoff then the foam was placed into a reticulator device comprising apressure chamber, the interior of which was isolated from thesurrounding atmosphere. The pressure in the chamber was reduced so as toremove substantially all the air in the cured foam. A mixture ofhydrogen and oxygen gas, present at a ratio of 2.3:1 H₂:O₂, sufficientto support combustion, was charged into the chamber. The pressure in thechamber was maintained above atmospheric pressure for a sufficient timeto ensure gas penetration into the foam. The gas in the chamber was thenignited by a spark plug and the ignition exploded the gas mixture withinthe foam. To minimize contact with any combustion products and to coolthe foam, the resulting combustion gases were removed from the chamberand replaced with gaseous nitrogen immediately after the explosion.Then, the above-described reticulation process was repeated one moretime. Without being bound by any particular theory, the explosions werebelieved to have at least partially removed or more likely substantiallyremoved many of the cell walls or “windows” between adjoining cells inthe foam, thereby creating inter-connected cells via open pores andleading to a reticulated elastomeric matrix structure and this processis known as thermal reticulation.

The average cell diameter or other largest transverse dimension ofDegradable Reticulated Elastomeric Matrix is expected to be about thesame (759 μm) as the unreticulated matrix; and the post-reticulationdensity was 3.60 lbs/ft³ (0.058 g/cc).

Fluid, e.g., liquid, permeability using water through ReticulatedDegradable Elastomeric Matrix was measured in the foam-rise directionand was determined to have an average of 619 Darcy. The permeabilityincreased by about 45× from the unreticulated that was crushed to thethermally reticulated biodegradable matrix showing that crushing did notproduce high permeability while thermal reticulation led to much higherpermeability brought about by the presence of a continuous void phasewhich itself is a result the network of cells interconnected via theopen pores therein and the subsequent communication andinterconnectivity.

The glass transition of the degradable elastomeric matrix was measuredby a temperature ramp between −80 C to 180 C at 2° C./minute using aQ800 Dynamic Mechanical Analyzer (TA Instruments, New Castle, Del.). Thesample dimensions were 16.3 mm 5.6 mm 2 2 mm; the frequency was 1 Hz andthe experiment was done in the tensile mode under a load of 0.02Newtons. The glass transition temperature as determined from peak in tandelta (which is equal to the ratio of dynamic viscous loss modulus :dynamic elastic storage modulus) was −14° C.

Example 3 Synthesis and Properties of Degradable Reticulated ElastomericMatrix Containing Polycaprolactone/Polyglycolide Copolymer Polyol

A reticulated partially resorbable elastomeric matrix was made by thefollowing procedure: The aromatic isocyanate MONDUR 1488 (from BayerMaterial Science) was used as the isocyanate component. MONDUR 1488 is aliquid at 25° C. MONDUR 1488 contains 4,4′-diphenylmethane diisocyanate(MDI) and 2,4′-MDI and has an isocyanate functionality of about 2.2 to2.3. A polycaprolactone/PGA copolymer diol with a molecular weight ofabout 3,000 Daltons, composed of a mole ratio of PCL:PGA of 70:30, wasused as the polyol component and was a viscous liquid at 25° C.Distilled water was used as the blowing agent. The catalysts used werethe amines triethylene diamine (33% by weight in dipropylene glycol;DABCO 33LV from Air Products) and bis(2-dimethylaminoethyl)ether (23% byweight in dipropylene glycol; NIAX A-133 from Momentive PerformanceChemicals). Silicone-based surfactants TEGOSTAB BF 2370, TEGOSTAB B5055,AND TEGOSTAB B8300 (from Evonik Degussa) were used for cellstabilization. A cell-opener was used (ORTEGOL 501 from Evonik Degussa).Glycerine (99.7% USP Grade) and 1,4-butanediol (99.75% by weight purity,from Lyondell) were added to the mixture as, respectively, across-linking agent and a chain extender. The proportions of theingredients that were used is given in Table IV below.

TABLE IV Ingredient Parts by Weight Polyol Component 100.00 IsocyanateComponent 45.58 Isocyanate Index 1.00 Cell Opener 3.00 Distilled Water1.60 BF2370 Surfactant 1.20 B8300 Surfactant 0.60 B5055 Surfactant 0.6033LV Catalyst 0.40 A-133 Catalyst 0.15 Glycerine 1.00 1,4-Butanediol1.50

The isocyanate index, a quantity well known in the art, is the moleratio of the number of isocyanate groups in a formulation available forreaction to the number of groups in the formulation that are able toreact with those isocyanate groups, e.g., the reactive groups ofdiol(s), polyol component(s), chain extender(s), water and the like,when present.

The polyol component was heated at 70° C. in a circulating-air oven, and50 g thereof was weighed out into a polyethylene cup. The remainingingredients, excluding the isocyanate were added to the polyol componentat their proportional weights based on the aforementioned formulation.These components were mixed together with a pin style high sheer mixerattached to a motor for 60 seconds.

The required amount of isocyanate was weighed into a polyethylene cupand then added to the polyol mixture during high speed mixing. The totalformulation was mixed vigorously with the drill mixer as described abovefor 10 seconds then poured into a Styrofoam bowl mold. The foamingprofile was as follows: 10 seconds mixing time, 30 seconds cream time,and 130 seconds rise time. The block was allowed to cure for 24 hours atambient conditions.

Following curing,the sides and bottom of the foam block were trimmed offthen the foam was placed into a reticulator device comprising a pressurechamber, the interior of which was isolated from the sin-roundingatmosphere. The pressure in the chamber was reduced so as to removesubstantially all the air in the cured foam. A mixture of hydrogen andoxygen gas, present at a ratio of 2.3:1 H₂:O₂, sufficient to supportcombustion, was charged into the chamber. The pressure in the chamberwas maintained above atmospheric pressure for a sufficient time toensure gas penetration into the foam. The gas in the chamber was thenignited by a spark plug and the ignition exploded the gas mixture withinthe foam. To minimize contact with any combustion products and to coolthe foam, the resulting combustion gases were removed from the chamberand replaced with gaseous nitrogen immediately after the explosion.Then, the above-described reticulation process was repeated one moretime. Without being bound by any particular theory, the explosions werebelieved to have at least partially removed many of the cell walls or“windows” between adjoining cells in the foam, thereby creating openpores and leading to a reticulated elastomeric matrix structure.

The entire disclosure of each and every U.S. patent and patentapplication, each foreign and international patent publication and eachother publication, and each unpublished patent application that isreferenced in this specification, or elsewhere in this patentapplication, is hereby specifically incorporated herein, in itsentirety, by the respective specific reference that has been madethereto.

While illustrative embodiments of the invention have been describedabove, it is understood that many and various modifications will beapparent to those in the relevant art, or may become apparent as the artdevelops. Such modifications are contemplated as being within the spiritand scope of the invention or inventions disclosed in thisspecification.

INDUSTRIAL UTILITY

This invention has industrial applicability in providinghydrolytically-cleavable polyurethane foams, methods of theirmanufacture, and devices fabricated therefrom.

INCORPORATION BY REFERENCE

Throughout this application, various references including publications,patents, and pre-grant patent application publications are referred to.Disclosures of these publications in their entireties are herebyincorporated by reference into this application to more fully describethe state of the art to which this invention pertains. It isspecifically not admitted that any such reference constitutes prior artagainst the present application or against any claims thereof. Allpublications, patents, and pre-grant patent application publicationscited in this specification are herein incorporated by reference, andfor any and all purposes, as if each individual publication or patentapplication were specifically and individually indicated to beincorporated by reference. In the case of inconsistencies the presentdisclosure will prevail.

1. A matrix comprising a biocompatible, cross-linked, biodegradable,elastomeric polyurethane, the matrix having a continuous-interconnectedvoid phase, wherein the matrix is configured to be in-grown by abiological tissue.
 2. The matrix of claim 1, wherein said elastomericmatrix is resilient.
 3. The matrix of claim 1, wherein said polyurethanematrix is reticulated to a Darcy permeability of at least
 200. 4. Thematrix of claim 1, wherein said polyurethane comprises a biodegradable,polyol-derived soft segment and an isocyanate-derived hard segment. 5.The matrix of claim 4, comprising an amount of glycerol to partiallycross-link said hard segment.
 6. The matrix of claim 4, wherein saidisocyanate-derived hard segment is substantially free of chemicalgroupings selected from the group consisting of biuret, allophanate, andisocyanurate groups.
 7. The matrix of claim 5, wherein saidisocyanate-derived hard segment is biostable.
 8. The matrix of claim 7,wherein said isocyanate hard segment is substantially non-crystalline.9. The matrix of claim 8, wherein said isocyanate hard segment comprises4,4-MDI and 2,4-MDI in a ratio to render said hard segment substantiallynon-crystalline.
 10. The matrix of claim 9 wherein said 2,4-MDI ispresent at from about 5% to about 50% relative to the amount of said4,4-MDI.
 11. The matrix of claim 4, wherein said isocyanate-derived hardsegment is biodegradable.
 12. The matrix of claim 11, wherein saidbiodegradable, isocyanate-derived hard segment comprises an aromaticdiisocyanate.
 13. The matrix of claim 12, wherein said aromaticdiisocyanate is a hydrolytically-cleavable, bridged diphenyldiisocyanate.
 14. The matrix of claim 11, wherein said biodegradable,isocyanate-derived hard segment comprises an aliphatic diisocyanate. 15.The matrix of claim 14, wherein said aliphatic diisocyanate is selectedfrom the group consisting of lysine methyl ester diisocyanate, lysinetriisocyanate, 1,4-diisocyanatobutane, and mixtures thereof.
 16. Thematrix of claim 4, wherein said hydrolysable polyol comprises at leastone moiety derived from a polycaprolactone polyol.
 17. The matrix ofclaim 1, wherein said matrix is reticulated.
 18. A process for preparinga biocompatible, cross-linked, biodegradable polyurethane, the matrixhaving a continuous-interconnected void phase, wherein said matrix isconfigured to be in-grown by a biological tissue the process comprising:providing a biodegradable polyol having a molecular weight of at least750; admixing an isocyanate component, wherein said isocyanate reacts toform substantially non-crystalline hard segments; admixing a glycerolcross-linker; admixing a blowing agent; and reacting said admixture toform a biocompatible, cross-linked, biodegradable polyurethane foam. 19.The process of claim 18, further comprising contacting saidpolyrurethane foam with an explosive mixture of hydrogen and oxygen. 20.The process of claim 19, further comprising reticulating said foam byigniting said explosive mixture.
 21. The process of claim 20, furthercomprising admixing at least one agent selected from the groupconsisting of cross-linking agents, chain extenders, catalysts, cellopeners, surfactants, and viscosity modifiers.
 22. A method of treatinga tissue defect comprising: providing a matrix to an in vivo site of atissue defect, said matrix comprising a biocompatible, cross-linked,biodegradable polyurethane, the matrix having acontinuous-interconnected void phase, wherein said matrix is configuredto be in-grown by a biological tissue.
 23. A medical device comprisingthe matrix of claim 1.